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Perspective

The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System

by
Nicole Denoix
1,2,
Oscar McCook
2,*,
Sarah Ecker
2,
Rui Wang
3,
Christiane Waller
4,
Peter Radermacher
2 and
Tamara Merz
2
1
Clinic for Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, 89081 Ulm, Germany
2
Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm University Medical Center, 89081 Ulm, Germany
3
Faculty of Science, York University, Toronto, ON M3J 1P3, Canada
4
Department of Psychosomatic Medicine and Psychotherapy, Nuremberg General Hospital, Paracelsus Medical University, 90419 Nuremberg, Germany
*
Author to whom correspondence should be addressed.
Antioxidants 2020, 9(8), 748; https://doi.org/10.3390/antiox9080748
Submission received: 6 July 2020 / Revised: 10 August 2020 / Accepted: 11 August 2020 / Published: 14 August 2020
(This article belongs to the Special Issue Hydrogen Sulfide in Biology)
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Abstract

:
The purpose of this review is to explore the parallel roles and interaction of hydrogen sulfide (H2S) and oxytocin (OT) in cardiovascular regulation and fluid homeostasis. Their interaction has been recently reported to be relevant during physical and psychological trauma. However, literature reports on H2S in physical trauma and OT in psychological trauma are abundant, whereas available information regarding H2S in psychological trauma and OT in physical trauma is much more limited. This review summarizes recent direct and indirect evidence of the interaction of the two systems and their convergence in downstream nitric oxide-dependent signaling pathways during various types of trauma, in an effort to better understand biological correlates of psychosomatic interdependencies.

1. Introduction

The gasotransmitter hydrogen sulfide (H2S) (endogenously produced by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate-sulfurtransferase (3MST) (as depicted in Figure 1)) and the neuroendocrine oxytocin (OT) system have been recently shown to not only possibly play parallel roles in the heart and the brain in response to trauma, but also to influence one another. Trauma can lead to cardiovascular impairments and disease which worsens the outcomes of intensive care patients and increases morbidity and mortality [1,2]. Trauma is either a consequence of a deep emotional pain or a physical injury. Psychological trauma is due to a strong emotional response to a life-threatening event. In contrast, physical trauma can be defined as physiological injury or an impact against the body. Current research underscores the fact that physical and psychological trauma share physiological correlates [3]. OT and H2S are relevant in models of both psychological and physical trauma, displaying cardio-protective, anti-oxidative and anti-inflammatory effects [4,5,6,7].
There is a dearth of information regarding the direct interaction between the H2S and OT systems: in human myometrial strip biopsies, sodium hydrosulfide (NaHS), a H2S releasing salt, decreased the frequency of oxytocin-induced myometrial contractions, mediated by ATP-sensitive potassium channels (KATP-channels) [10]. You et al., reported an inverse correlation between CSE and oxytocin receptor (OTR) expression patterns in the myometrium in pregnant women at term before or after the onset of labor [11]. They also showed that both H2S produced locally and exogenously administered NaHS were able to suppress OTR expression and activate phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated protein kinase (ERK) and KATP-channels in pregnant human myometrial cells [11]. Finally, in a CSE knock out (CSEko) model, Akahoshi et al. were able to show that pregnant mice presenting with preeclampsia-like symptoms displayed dysfunctional contraction of the mammary myoepithelial cells, which was attributed to decreased OTR, and also had impaired uterine contraction responses to OT [12]. The paucity of literature on this subject is a limitation, which led us to investigate parallel roles for the two systems, in the heart and brain, which may suggest their interaction. Specifically, this review explores the literature on both H2S and OT systems to help to shed light on their interaction in the regulation of fluid balance, blood volume [4,13], blood pressure [14,15,16,17] and heart rate [18,19].

2. The Neuroendocrine Control of Fluid Hemostasis

The hypothalamus is the central integrative structure for the regulation of blood and body fluid volume and osmolality [20]. In response to changes of the peripheral fluid homeostasis, the hypothalamus regulates the blood pressure and heart rate [4]. The supraoptic (SON) and paraventricular nuclei (PVN) are of particular interest with regard to the interaction of the H2S and OT systems in the regulation of fluid homeostasis [4]. In trans-ascending aortic constriction rat models of heart failure, chronic selective activation of PVN neurons producing OT was effective in increasing cardiac parasympathetic tone and ameliorating the loss of heart function and myocardial injury [21,22]. H2S has been reported to depolarize magnocellular neurons of the PVN in a dose–response fashion, hinting at its possible role in regulating autonomic and endocrine functions [23]. Moreover, in water deprived (24 h) rats, an intracerebroventricular injection of sodium sulfide (Na2S), another H2S-releasing salt, led to increases plasma concentrations of OT and a decrease of hypothalamic nitrate/nitrite [4]. The authors concluded that H2S regulates the roles of both the behavioral and neuroendocrine responses to water deprivation independently of nitric oxide (NO) and stimulates OT secretion by inhibiting the NO system [4]. In a more recent study, in rat hypothalamic explants H2S was also shown to be a (positive) regulator of OT in response to acute osmotic stimulus, whereas NO played a key role as a negative neuroendocrine modulator of OT [24]. Additionally, Coletti et al. localized constitutive expression of CBS in the rat hypothalamic SON and PVN, but an important omission in this model which may limit their findings was that they did not look for the interaction of CSE [24]. This omission assumes importance when considering the complex interaction of CSE and CBS, which were found to be expressed in an inverse fashion after cerebral injury [25]. A further word of caution is warranted regarding the translational value of the above experiments [4,22,23,24]: they were all performed in rat models, and some of them on tissue explants. Ex vivo studies in general are a limited representation of the in vivo situation, and rats may not be the most appropriate model organism to study the effects of NO interactions, considering their much higher NO levels. Endogenous NO production in rats is at least an order of magnitude greater than in pigs and humans [26], suggesting that the results here may only be applicable to the rat.
In a clinically relevant porcine hemorrhagic shock study [27], variable expressions of OT, OTR, CSE and CBS were also identified immunohistochemically to be co-localized in the hypothalamic SON and PVN regions in magnocellular neurons, parenchyma, arteries and microvasculature (see Figure 2A). Hemorrhagic shock has been shown to induce hypothalamic OT release [28] and H2S can also stimulate hypothalamic OT release [4]. Thus, the colocalization of CSE, CBS, OT and OTR in the hypothalamus may be indicative of H2S stimulating the release of OT as a consequence of the dramatic fluid shifts generated by the hemorrhagic shock (see Figure 2B). Finally, it is tempting to speculate that endogenous H2S is involved in the hemorrhagic shock-induced OT release, although it is not yet clear how hemorrhagic shock affects the cerebral expression levels of the H2S-producing enzymes (CSE and CBS). Recently, in a porcine model of acute subdural hematoma-induced acute brain injury with resuscitation and neuro intensive care maintenance, Denoix et al. characterized the spatial expression pattern for the OT/OTR and the endogenous H2S-producing enzymes [25]. The authors found OT/OTR, CSE and CBS to be present in neurons, the vasculature and the parenchyma at the base of sulci. This finding might assume particular importance for translational purposes, because the base of the sulci is exactly where pressure-induced edema formation is reported to be found in the gyrencephalic human brain, which is not possible to investigate in the lissencephalic rodent brain [25]. Interestingly, the parenchyma and the cortical neurons in the gyri were positive for CSE but its expression was reduced with injury [25]. CBS, OT and OTR displayed an opposite pattern of expression to CSE and were upregulated with injury. The differential regulation of these enzymes suggests a much more complex relationship between the OT and H2S systems in osmotic regulation than what was reported previously [4,24].
Furthermore, H2S has been reported to improve the integrity of the barrier and attenuate cerebral edema, and the reduction of CSE expression close to injury sites coincided with increased Alb extravasation and barrier dysfunction [29,30,31]. Denoix et al. reported that OTR and CSE were also expressed in the arteries and microvasculature, suggesting that they might play a role in blood–brain barrier integrity [25]. The presence of OT/OTR in areas of acute subdural hematoma-induced injury reported by Denoix et al. is in line with OTR upregulation observed in humans, as an adaptive stress response in “vascular profiles” associated with perivascular swelling and around micro-infarcts [25,32].

3. H2S in Cardiac and Vascular Protection

Recently, in a mouse model of acute-on-chronic disease, Merz et al. showed that for mice with homozygous global deletion of CSE (CSEko) (generated by [17]), the main H2S producing enzyme in the cardiovascular system, chronically exposed to cigarette smoke prior to undergoing acute thorax trauma, displayed decreased OTR expression in the heart, which was attenuated by the administration of the slow-H2S-releasing compound GYY4137 [19]. Furthermore, these CSEko mice had significantly higher heart rates and blood pressure than wild type (WT) animals, and reduced OTR expression (see Figure 3A), supporting the important role of CSE expression in the cardiovascular system [16,17,19].
There are a plethora of fairly recent reviews on H2S and its protective effects in the cardiovascular system [7,33,34,35,36,37,38,39]. Endogenous H2S production or expression of H2S-producing enzymes (primarily CSE) has been reported in the following cell types of the cardiovascular system: smooth muscle cells, cardiomyocytes, endothelial cells and immune cells [8,19,25,40,41]. H2S has been shown to play a decisive role in the modulation of the cardiovascular system, i.e., as an endogenous activator of angiogenesis [8,42] via hypothalamic control [4], and a basal vasorelaxant, blood pressure and heart rate regulator [43,44]. Downstream signaling cascades involved in mediating H2S-dependent vaso-active effects activate KATP-channels and stimulate Akt-dependent endothelial eNOS. Furthermore, H2S can induce antioxidant effects via the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which can be also regulated by OT [7,45,46,47]. H2S administration in rodents ameliorated myocardial fibrosis and oxidative stress in hypertension [48], and had beneficial effects on a myocardial infarct [15,49,50,51,52]. NaHS administration in rats significantly attenuated hemorrhagic shock-induced metabolic acidosis and simultaneously downregulated inducible nitric oxide synthase (iNOS) expression and NO production in the heart and aorta [53]. A murine model of combined blunt chest trauma and subsequent hemorrhagic shock showed that administration of the slow-releasing mitochondria targeted H2S donor AP39 during the resuscitation period and reduced lung tissue iNOS expression; however, it aggravated circulatory shock-induced hypotension due to its vasodilator capacities [54]. The complex interaction of H2S and NO in inflammation has been reviewed previously [55]. The H2S and OT systems share downstream signaling cascades that converge on the same NOS/NO-dependent pathway, which is further support of their interaction/relationship [7,56].
In large animal models, in general, the effects of H2S administration have been less robust than those seen in the rodent models. Sulfide administration in long-term porcine hemorrhage and resuscitation reduced mortality and attenuated organ dysfunction and injury, but its effectiveness in this model was restricted to a narrow timing and dosing window [57]. Other authors showed no benefit at all: intravenous Na2S did not induce hypothermia or improve survival from hemorrhagic shock in pigs [58,59]. Thus, for the clinical development of H2S-based therapies, which might potentially also affect OT/OTR signaling, further research is warranted.

4. OT/OTR in Cardiac and Vascular Protection

In contrast to the highly-diffusible, gaseous H2S, which does not require any membrane receptor [60], the OT system comprises a ligand–receptor (G protein-coupled) interaction. Upon OT binding to OTR, it can stimulate pro-survival kinases such as ERK and PI3K/Akt, which can in turn activate eNOS or CSE (H2S) [56]. OT can, furthermore, signal through calmodulin-dependent protein kinase II (CaMK II), regulating Ca2+ homeostasis, necessary for cardiomyocyte function [56]. OTR expression has been detected in cardiomyocytes, vasculature (smooth muscle cells and endothelium), macrophages, peripheral blood mononuclear cells and cardiac fibroblasts [19,61,62,63,64,65,66,67]. The role of OT in the heart has been recently reviewed [61,68], and interestingly enough OT shares many of the properties also reported for H2S, e.g., increase of glucose uptake in cardiac cells, anti-inflammatory and antioxidant activity [69,70,71], blood pressure lowering capacities via NO-mediated vasodilation [72], negative inotropic and chronotropic effects, natriuretic effects and effects on endothelial cell growth [14,68,73,74]. The NO-mediated vasodilatory effects of OT are also reported to regulate blood pressure [68,75,76,77,78] and body fluid homeostasis, albeit through an interaction with H2S [4,24].
Subcutaneous OT administration in myocardial infarct resulted in reduced inflammation, apoptosis, and ultimately ameliorated heart function [79,80,81,82]. Finally, downregulation of the OT system is associated with dilated cardiomyopathy [83], hypertension [84] and impaired cardiovascular function [19,46,68,80]. In a porcine myocardial infarct model, placebo-treated animals with high endogenous OT levels at the start of the experiment had better ejection fraction overall compared to OT-treated animals with high basal endogenous OT levels [85]. In contrast, in the low endogenous OT group receiving exogenous OT had no effect on cardiac function or cardiac OTR expression [85], yet the group with low basal OT levels without OT treatment had reduced function and larger infarct size [85]. Thus, the potential of OT to exert its cardio-protective effects seems to be at least in part dependent on the presence of both its basal receptor and its ligand.

5. Chronic Cardiovascular Disease

Administrations of both H2S [45,86,87] and OT [88,89] have been shown to reduce atherosclerotic plaque formation and to decrease the pro-inflammatory response—OT specifically through the upregulation of its receptor. Impaired endogenous H2S release is reported to be a key mediator with regard to the development of chronic cardiovascular pathology [8]. In a clinically relevant resuscitated model of septic shock, familial hypercholesterolemia Bretoncelles Meishan (FBM) swine, a comorbid large animal strain characterized by a clinical phenotype resembling the human atherosclerotic patient [90,91] with coronary artery disease, presented with elevated nitrotyrosine formation, a marker of nitrosative and oxidative stress, and significantly lowered CSE and OTR protein expression levels in the myocardium, which coincided with altered cardiac function [41,46]. Interestingly, already without septic shock, the FBM pig strain displayed decreased CSE expression in the media of the coronary artery and elevated nitrotyrosine formation [40]. The septic shock was associated with an even more pronounced downregulation of CSE [40]. Overall, these observations agree well with the fact that atherosclerosis and hypertension are associated with reduced levels of CSE [86]. Finally, CSE is proposed to modulate OTR in a tissue and function dependent manner during the progression of atherosclerosis [56]. The RISK pathway has been suggested to be the downstream molecular pathway, where H2S and OT signaling converge in atherosclerosis and cardioprotection (see Figure 3B, [56]). RISK activation leads to PI3K Akt, eNOS cascades and ERK 1/2 activation [56], which in turn promotes reperfusion by stimulating cell migration and angiogenesis. The PI3K/Akt cascades are also activated through H2S and are reported to promote myocardial protection [92]. These signaling pathways for H2S-mediated and OT-mediated myocardial protection were identified in animal models [56,92], but might also be relevant in human cardioprotection. Even though studies in human myocardial tissue are still lacking, the fact that H2S and OT activate the same downstream targets in human myometrial samples [10,11] supports this hypothesis. The RISK pathway is active in endothelial cells and cardiomyocytes. In endothelial cells, the activation of eNOS/NO as an angiogenic and vasodilating factor is crucial. In other cells, such as cardiomyocytes, RISK-activated pathways regulating apoptosis and antioxidant signaling play a role.
Interestingly, insulin receptors also act via the PI3K/Akt signaling pathway [93], and both OT and H2S are involved in the modulation of energy homeostasis and glucose metabolism (reviewed recently for OT [94] and H2S [95]). OT, CSE and CBS are expressed in insulin-sensitive tissues [95,96]. H2S is endogenously released by skeletal muscle, liver, adipose and islet-β-cells [97]; the OT and OTR are also present in islet-β-cells and skeletal muscle cells [98]. OT has been reported to increase glucose uptake in cardiomyocytes via PI3K signaling [96]; exogenous H2S administration restored blood glucose levels in the previously mentioned CSEko mice, and was associated with an upregulation of cardiac OTR [19]. Hyperglycemia, in turn, can reduce the expression of CSE [99] and suppress OT [68,100]. Low levels of OT and H2S are associated with diabetes and insulin resistance [68,95]. It is striking to observe that chronic co-morbidities in particular seem to have common ground in the interaction of H2S and OT.

6. The Role of OT/OTR in the Brain and Cardiovascular System during Psychological Stress

Psychological stress, e.g., early life stress, is well established as a risk factor for developing cardiovascular diseases [56,101,102,103,104]. The OT/OTR system is associated with stress-related responses, anxiolytic effects, maternal behavior, optimistic-belief updating, optimism and social reward perception, and it has been extensively studied in psychosomatic medicine [66,105,106]. Psychological stress was shown to increase heart rate and blood pressure, and the chemical blockade of the OTR worsens the cardiovascular response to stress [107,108,109,110]. An intracerebral injection of OTR antagonist attenuated the increase in heart rate after stress, but had no effect in the basal state without stress [110,111]. This suggests that multiple factors may be at play in the regulation of the OT system, stress being one of them, affecting endogenous receptor ligand levels and ultimately the physiological response.
OT plasma levels were positively related to improved cardiovascular and sympathetic responses to stress [112]. In mice, early life stress led to a significant long-term reduction of both cardiac CSE and OTR expression to the same degree [113]. Moreover, OTR knock out (OTRko) mice presented with reduced cardiac CSE expression, providing another confirmation of the link between the OT and H2S systems [113]. Interestingly, OTR expression was dependent on the “stress-dose”, inasmuch as “long-term” stressed (LTSS) mice had decreased OTR protein expression, whereas the “short-term” stressed (STSS) group displayed increased OTR expression [113]. This led the authors to conclude that the LTSS group with reduced OTR expression reflects increased vulnerability, whereas the STSS with higher receptor expression may indicate an adaptive response conferring resilience [113].
This provides evidence that the type of stress has an important impact on the OT ligand and its receptor modulation. In addition to the fact that the loss of trauma-related OTR in cardiac tissue was attenuated with administration of exogenous H2S [19], the interaction of the OT/OTR and the H2S/CSE systems in the context of psychological trauma was highlighted by the protective effect of exogenous H2S on early life stress-related colonic inflammation [114]. In turn, OT administration also exerted colon-protective effects through similar anti-oxidative and anti-inflammatory properties [115]. The therapeutic potentials of H2S and OT are beyond the scope of this work, but have been reviewed recently [56,116,117,118].

7. Conclusions

When reviewing the literature, it is striking that there is a disparity of studies of the H2S and OT system: there are plenty of reports on the role of H2S in physical trauma and OT in psychological trauma, whereas investigations of the role of H2S in psychological trauma and OT in physical trauma are rather limited. The current knowledge is not sufficient to speculate about treatment options; thus, this imbalance in studies should be addressed by researchers in the future. H2S and OT have parallel effects suggesting an interaction of the two systems. Both the H2S/CSE and OT/OTR systems assume major importance in the regulation of blood pressure and circulating blood volume. Moreover, there is evidence for their interaction with one another in peripheral organs, particularly in the heart. Finally, the two systems share signaling cascades that converge on the same signaling pathway. The interaction of the two systems seems to regard both psychological disorders and cardiovascular disease, and, hence, understanding more of the way that the H2S/CSE and OT/OTR systems work as mediators in stress may contribute to tackling the mutual interplay between body and mind.

Author Contributions

Conceptualization, O.M. and T.M.; writing—original draft preparation, N.D.; writing—review and editing, O.M., S.E., R.W., C.W., P.R. and T.M.; visualization, N.D.; supervision, P.R.; project administration, O.M.; funding acquisition, R.W., P.R. and T.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Deutsche Forschungsgemeinschaft (DFG), grant number Project-ID 251293561-Collaborative Research Center (CRC) 1149 to P.R. and T.M., and the DFG-funded Graduiertenkolleg “PulmoSens” GRK 2203 to P.R., R.W. has been funded by a Discovery grant from Natural Sciences and Engineering Council of Canada.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Wang, C.-J.; Chen, Y.-C.; Chien, T.-H.; Chang, H.-Y.; Chen, Y.-H.; Chien, C.-Y.; Huang, T.-S. Impact of comorbidities on the prognoses of trauma patients: Analysis of a hospital-based trauma registry database. PLoS ONE 2018, 13, e0194749. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Ferraris, V.A.; Ferraris, S.P.; Saha, S.P. The relationship between mortality and preexisting cardiac disease in 5971 trauma patients. J Trauma Acute Care Surg. 2010, 69, 645–652. [Google Scholar] [CrossRef]
  3. Auxéméry, Y. Post-traumatic psychiatric disorders: PTSD is not the only diagnosis. Presse. Med. 2018, 47. [Google Scholar] [CrossRef] [PubMed]
  4. Coletti, R.; Almeida-Pereira, G.; Elias, L.L.K.; Antunes-Rodrigues, J. Effects of hydrogen sulfide (H2S) on water intake and vasopressin and oxytocin secretion induced by fluid deprivation. Horm. Behav. 2015, 67, 12–20. [Google Scholar] [CrossRef]
  5. Gouin, J.P.; Carter, C.S.; Pournajafi-Nazarloo, H.; Glaser, R.; Malarkey, W.B.; Loving, T.J.; Stowell, J.; Kiecolt-Glaser, J.K. Marital behavior, oxytocin, vasopressin, and wound healing. Psychoneuroendocrinology 2010, 35, 1082–1090. [Google Scholar] [CrossRef] [Green Version]
  6. Olff, M.; Frijling, J.L.; Kubzansky, L.D.; Bradley, B.; Ellenbogen, M.A.; Cardoso, C.; Bartz, J.A.; Yee, J.R.; van Zuiden, M. The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences. Psychoneuroendocrinology 2013, 38, 1883–1894. [Google Scholar] [CrossRef] [Green Version]
  7. Polhemus, D.J.; Lefer, D.J. Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease. Circ. Res. 2014, 114, 730–737. [Google Scholar] [CrossRef]
  8. Wang, R. Physiological implications of hydrogen sulfide: A whiff exploration that blossomed. Physiol. Rev. 2012, 92, 791–896. [Google Scholar] [CrossRef] [Green Version]
  9. Marutani, E.; Ichinose, F. Emerging pharmacological tools to control hydrogen sulfide signaling in critical illness. Intensive Care Med. Exp. 2020, 8, 5. [Google Scholar] [CrossRef] [Green Version]
  10. Hu, R.; Lu, J.; You, X.; Zhu, X.; Hui, N.; Ni, X. Hydrogen sulfide inhibits the spontaneous and oxytocin-induced contractility of human pregnant myometrium. Gynecol. Endocrinol. 2011, 27, 900–904. [Google Scholar] [CrossRef]
  11. You, X.; Chen, Z.; Zhao, H.; Xu, C.; Liu, W.; Sun, Q.; He, P.; Gu, H.; Ni, X. Endogenous hydrogen sulfide contributes to uterine quiescence during pregnancy. Reproduction 2017, 153, 535–543. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Akahoshi, N.; Handa, H.; Takemoto, R.; Kamata, S.; Yoshida, M.; Onaka, T.; Ishii, I. Preeclampsia-Like Features and Partial Lactation Failure in Mice Lacking Cystathionine γ-Lyase-An Animal Model of Cystathioninuria. Int. J. Mol. Sci. 2019, 20, 3507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Ruginsk, S.G.; Mecawi, A.S.; da Silva, M.P.; Reis, W.L.; Coletti, R.; de Lima, J.B.; Elias, L.L.; Antunes-Rodrigues, J. Gaseous modulators in the control of the hypothalamic neurohypophyseal system. Physiology 2015, 30, 127–138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Bernatova, I.; Rigatto, K.V.; Key, M.P.; Morris, M. Stress-induced pressor and corticosterone responses in oxytocindeficient mice. Exp. Physiol. 2004, 89, 549–557. [Google Scholar] [CrossRef] [PubMed]
  15. Ellmers, L.J.; Templeton, E.M.; Pilbrow, A.P.; Frampton, C.; Ishii, I.; Moore, P.K.; Bhatia, M.; Richards, A.M.; Cameron, V.A. Hydrogen Sulfide Treatment Improves Post-Infarct Remodeling and Long-Term Cardiac Function in CSE Knockout and Wild-Type Mice. Int. J. Mol. Sci. 2020, 21, 4284. [Google Scholar] [CrossRef]
  16. Hartmann, C.; Hafner, S.; Scheuerle, A.; Möller, P.; Huber-Lang, M.; Jung, B.; Nussbaum, B.; McCook, O.; Gröger, M.; Wagner, F.; et al. The role of cystathionine-γ-lyase in blunt chest trauma in cigarette smoke exposed mice. Shock 2017, 47, 491–499. [Google Scholar] [CrossRef]
  17. Yang, G.; Wu, L.; Jiang, B.; Yang, W.; Qi, J.; Cao, K.; Meng, Q.; Mustafa, A.K.; Mu, W.; Zhang, S.; et al. H2S as a physiologic vasorelaxant: Hypertension in mice with deletion of cystathionine gamma-lyase. Science 2008, 322, 587–590. [Google Scholar] [CrossRef] [Green Version]
  18. Hicks, C.; Ramos, L.; Reekie, T.; Misagh, G.H.; Narlawar, R.; Kassiou, M.; McGregor, S. Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non-peptide oxytocin receptor agonist WAY 267,464: A biotelemetry study in rats. Br. J. Pharm. 2014, 171, 2868–2887. [Google Scholar] [CrossRef] [Green Version]
  19. Merz, T.; Lukaschewski, B.; Wigger, D.; Rupprecht, A.; Wepler, M.; Gröger, M.; Hartmann, C.; Whiteman, M.; Szabo, C.; Wang, R.; et al. Interaction of the hydrogen sulfide system with the oxytocin system in the injured mouse heart. Intensive Care Med. Exp. 2018, 6, 41. [Google Scholar] [CrossRef] [Green Version]
  20. Horn, E.M.; Waldrop, T.G. Oxygen-sensing neurons in the caudal hypothalamus and their role in cardiorespiratory control. Respir. Physiol. 1997, 110, 219–228. [Google Scholar] [CrossRef]
  21. Dyavanapalli, J.; Rodriguez, J.; Rocha Dos Santos, C.; Escobar, J.B.; Dwyer, M.K.; Schloen, J.; Lee, K.M.; Wolaver, W.; Wang, X.; Dergacheva, O.; et al. Activation of Oxytocin Neurons Improves Cardiac Function in a Pressure-Overload Model of Heart Failure. JACC Basic. Transl. Sci. 2020, 5, 484–497. [Google Scholar] [CrossRef] [PubMed]
  22. Garrott, K.; Dyavanapalli, J.; Cauley, E.; Dwyer, M.K.; Kuzmiak-Glancy, S.; Wang, X.; Mendelowitz, D.; Kay, M.W. Chronic activation of hypothalamic oxytocin neurons improves cardiac function during left ventricular hypertrophy-induced heart failure. Cardiovasc. Res. 2017, 113, 1318–1328. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Khademullah, C.S.; Ferguson, A.V. Depolarizing actions of hydrogen sulfide on hypothalamic paraventricular nucleus neurons. PLoS ONE 2013, 8, e64495. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Coletti, R.; de Lima, J.; Vechiato, F.; de Oliveira, F.L.; Debarba, L.K.; Almeida-Pereira, G.; Elias, L.; Antunes-Rodrigues, J. Nitric oxide acutely modulates hypothalamic and neurohypophyseal carbon monoxide and hydrogen sulphide production to control vasopressin, oxytocin and atrial natriuretic peptide release in rats. J. Neuroendocr. 2019, 31, e12686. [Google Scholar] [CrossRef]
  25. Denoix, N.; Merz, T.; Unmuth, S.; Hoffmann, A.; Nespoli, E.; Scheuerle, A.; Huber-Lang, M.; Gündel, H.; Waller, C.; Radermacher, P.; et al. Cerebral immunohistochemical characterization of the H2S and the Oxytocin systems in a porcine model of acute subdural hematoma. Front. Neurol. 2020, 11, 649. [Google Scholar] [CrossRef]
  26. Reade, M.C.; Young, J.D. Of mice and men (and rats): Implications of species and stimulus differences for the interpretation of studies of nitric oxide in sepsis. Br. J. Anaesth. 2003, 90, 115–118. [Google Scholar] [CrossRef] [Green Version]
  27. Datzmann, T.; Hoffmann, A.; McCook, O.; Merz, T.; Wachter, U.; Preuss, J.; Vettorazzi, S.; Calzia, E.; Gröger, M.; Kohn, F.; et al. Effects of sodium thiosulfate (Na2S2O3) during resuscitation from hemorrhagic shock in swine with preexisting atherosclerosis. Pharm. Res. 2020, 151, 104536. [Google Scholar] [CrossRef]
  28. Ciosek, J.; Cisowska, A.; Dabrowski, R. Galanin affects vasopressin and oxytocin release from the hypothalamo-neurohypophysial system in haemorrahaged rats. J. Physiol. Pharm. 2003, 54, 233–246. [Google Scholar]
  29. Stenzel, T.; Weidgang, C.; Wagner, K.; Wagner, F.; Gröger, M.; Weber, S.; Stahl, B.; Wachter, U.; Vogt, J.; Calzia, E.; et al. Association of Kidney Tissue Barrier Disrupture and Renal Dysfunction in Resuscitated Murine Septic Shock. Shock 2016, 46, 398–404. [Google Scholar] [CrossRef]
  30. Webb, G.D.; Lim, L.H.; Oh, V.M.S.; Yeo, S.B.; Cheong, Y.P.; Ali, M.Y.; Oakley, R.E.; Lee, C.N.; Wong, P.S.; Caleb, M.G.; et al. Contractile and vasorelaxant effects of hydrogen sulfide and its biosynthesis in the human mammary artery. J. Pharm. Exp. 2008, 324, 876–882. [Google Scholar] [CrossRef]
  31. Wen, J.Y.; Wang, M.; Li, Y.N.; Jiang, H.H.; Sun, X.J.; Chen, Z.W. Vascular Protection of Hydrogen Sulfide on Cerebral Ischemia/Reperfusion Injury in Rats. Front. Neurol. 2009, 9, 779. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. McKay, E.C.; Beck, J.S.; Khoo, S.K.; Dykema, K.J.; Cottingham, S.L.; Winn, M.E.; Paulson, H.L.; Lieberman, A.P.; Counts, S.E. Peri-Infarct Upregulation of the Oxytocin Receptor in Vascular Dementia. J. Neuropathol. Exp. Neurol. 2019, 78, 436–452. [Google Scholar] [CrossRef] [PubMed]
  33. Huang, S.; Li, H.; Ge, J. A cardioprotective insight of the cystathionine γ-lyase/hydrogen sulfide pathway. Int. J. Cardiol. Heart Vasc. 2015, 7, 51–57. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Meng, G.; Ma, Y.; Xie, L.; Ferro, A.; Ji, Y. Emerging role of hydrogen sulfide in hypertension and related cardiovascular diseases. Br. J. Pharm. 2014, 172, 5501–5511. [Google Scholar] [CrossRef]
  35. Wang, X.H.; Wang, F.; You, S.J.; Cao, Y.J.; Cao, L.D.; Han, Q.; Liu, C.F.; Hu, L.F. Dysregulation of cystathionine γ-lyase (CSE)/hydrogen sulfide pathway contributes to ox-LDL induced inflammation in macrophage. Cell Signal. 2013, 25, 2255–2262. [Google Scholar] [CrossRef]
  36. Whiteman, M.; Moore, P.K. Hydrogen sulfide and the vasculature: A novel vasculoprotective entity and regulator of nitric oxide bioavailability? J. Cell. Mol. Med. 2009, 13, 488–507. [Google Scholar] [CrossRef]
  37. Xu, Y.; Du, H.P.; Li, J. Statins upregulate cystathionine γ-lyase transcription and H2S generation via activating Akt signaling in macrophage. Pharm. Res. 2014, 87, 18–25. [Google Scholar] [CrossRef]
  38. Yu, X.H.; Cui, L.B.; Wu, K.; Zheng, X.L.; Cayabyab, F.S.; Chen, Z.W.; Tang, C.K. Hydrogen sulfide as a potent cardiovascular protective agent. Clin. Chim. Acta 2014, 437, 78–87. [Google Scholar] [CrossRef]
  39. Zheng, Y.; Ji, X.; Ji, K.; Wang, B. Hydrogen sulfide prodrugs-a review. Acta Pharm. Sin. B 2015, 5, 367–377. [Google Scholar] [CrossRef] [Green Version]
  40. Merz, T.; Stenzel, T.; Nussbaum, B.; Wepler, M.; Szabo, C.; Wang, R.; Radermacher, P.; McCook, O. Cardiovascular disease and resuscitated septic shock lead to the downregulation of the H2Sproducing enzyme cystathionine-γ- lyase in the porcine coronary artery. Intensive Care Med. Exp. 2017, 5, 17. [Google Scholar] [CrossRef] [Green Version]
  41. Nussbaum, B.L.; McCook, O.; Hartmann, C.; Matallo, J.; Wepler, M.; Antonucci, E.; Kalbitz, M.; Huber-Lang, M.; Georgieff, M.; Calzia, E.; et al. Left ventricular function during porcine resuscitated septic shock with pre-existing atherosclerosis. Intensive Care Med. Exp. 2016, 4, 14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Van Den Born, J.C.; Mencke, R.; Conroy, S.; Zeebregts, C.J.; Van Goor, H.; Hillebrands, J.L. Cystathionine Gamma-lyase is expressed in human atherosclerotic plaque microvessels and is involved in micro-angiogenesis. Sci. Rep. 2016, 6, 1–13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Dawe, G.S.; Han, S.P.; Bian, J.S.; Moore, P.K. Hydrogen sulphide in the hypothalamus causes an ATP-sensitive K channel-dependent decrease in blood pressure in freely moving rats. Neuroscience 2008, 152, 169–177. [Google Scholar] [CrossRef] [PubMed]
  44. Liu, W.Q.; Chai, C.; Li, X.Y.; Yuan, W.J.; Wang, W.Z.; Lu, Y. The cardiovascular effects of central hydrogen sulfide are related to K(ATP) channels activation. Physiol. Res. 2011, 60, 729–738. [Google Scholar] [CrossRef]
  45. Li, L.; Rose, P.; Moore, P.K. Hydrogen Sulfide and Cell Signaling. Annu. Rev. Pharm. Toxicol. 2011, 51, 169–187. [Google Scholar] [CrossRef] [Green Version]
  46. Merz, T.; Denoix, N.; Wigger, D.; Waller, C.; Wepler, M.; Vettorazzi, S.; Tuckermann, J.; Radermacher, P.; McCook, O. The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis. Front. Endocrinol. 2020, 11, 299. [Google Scholar] [CrossRef]
  47. Cho, S.Y.; Kim, A.Y.; Kim, J.; Choi, D.H.; Son, E.D.; Shin, D.W. Oxytocin alleviates cellular senescence through oxytocin receptor-mediated extracellular signal-regulated kinase/Nrf2 signalling. Br. J. Derm. 2019, 181, 1216–1225. [Google Scholar] [CrossRef]
  48. Meng, G.; Wang, J.; Xiao, Y.; Bai, W.; Xie, L.; Shan, L.; Moore, P.K.; Ji, Y. GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis in rats. J. Biomed. Res. 2015, 29, 203–213. [Google Scholar] [CrossRef] [Green Version]
  49. Chatzianastasiou, A.; Bibli, S.I.; Andreadou, I.; Efentakis, P.; Kaludercic, N.; Wood, M.E.; Whiteman, M.; Di Lisa, F.; Daiber, A.; Manolopoulos, V.G.; et al. Cardioprotection by H2S donors: Nitric oxide-dependent and -independent mechanisms. J. Pharm. Exp. 2016, 358, 431–440. [Google Scholar] [CrossRef] [Green Version]
  50. Karwi, Q.G.; Whiteman, M.; Wood, M.E.; Torregrossa, R.; Baxter, G.F. Pharmacological postconditioning against myocardial infarction with a slow-releasing hydrogen sulfide donor, GYY4137. Pharm. Res. 2016, 111, 442–451. [Google Scholar] [CrossRef] [Green Version]
  51. Lilyanna, S.; Peh, M.T.; Liew, O.W.; Wang, P.; Moore, P.K.; Richards, A.M.; Martinez, E.C. GYY4137 attenuates remodeling, preserves cardiac function and modulates the natriuretic peptide response to ischemia. J. Mol. Cell. Cardiol. 2015, 87, 27–37. [Google Scholar] [CrossRef] [PubMed]
  52. Sun, X.; Wang, W.; Dai, J.; Jin, S.; Huang, J.; Guo, C.; Wang, C.; Pang, L.; Wang, Y. A Long-Term and Slow-Releasing Hydrogen Sulfide Donor Protects against Myocardial Ischemia/Reperfusion Injury. Sci. Rep. 2017, 7, 3541. [Google Scholar] [CrossRef] [PubMed]
  53. Ganster, F.; Burban, M.; Bourdonnaye, M.; Fizanne, L.; Douay, O.; Loufrani, L.; Mercat, A.; Calès, P.; Radermacher, P.; Henrion, D.; et al. Effects of hydrogen sulfide on hemodynamics, inflammatory response and oxidative stress during resuscitated hemorrhagic shock in rats. Crit. Care 2010, 14, R165. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Wepler, M.; Merz, T.; Wachter, U.; Vogt, J.; Calzia, E.; Scheuerle, A.; Möller, P.; Gröger, M.; Kress, S.; Fink, M.; et al. The Mitochondria-Targeted H2Sdonor AP39 in a Murine Model of Combined Hemorrhagic Shock and Blunt Chest Trauma. Shock 2018, 52, 230–239. [Google Scholar] [CrossRef]
  55. Lo Faro, M.L.; Fox, B.; Whatmore, J.L.; Winyard, P.G.; Whiteman, M. Hydrogen sulfide and nitric oxide interactions in inflammation. Nitric Oxide 2014, 41, 38–47. [Google Scholar] [CrossRef]
  56. Wang, P.; Wang, S.C.; Yang, H.; Lv, C.; Jia, S.; Liu, X.; Wang, X.; Meng, D.; Qin, D.; Zhu, H.; et al. Therapeutic Potential of Oxytocin in Atherosclerotic Cardiovascular Disease: Mechanisms and Signaling Pathways. Front. Neurosci. 2019, 13, 454. [Google Scholar] [CrossRef] [Green Version]
  57. Bracht, H.; Scheuerle, A.; Gröger, M.; Hauser, B.; Matallo, J.; McCook, O.; Seifritz, A.; Wachter, U.; Vogt, J.A.; Asfar, P.; et al. Effects of intravenous sulfide during resuscitated porcine hemorrhagic shock. Crit. Care Med. 2012, 40, 2157–2167. [Google Scholar] [CrossRef]
  58. Derwall, M.; Westerkamp, M.; Löwer, C.; Deike-Glindemann, J.; Schnorrenberger, N.K.; Coburn, M.; Nolte, K.W.; Gaisa, N.; Weis, J.; Siepmann, K.; et al. Hydrogen sulfide does not increase resuscitability in a porcine model of prolonged cardiac arrest. Shock 2010, 34, 190–195. [Google Scholar] [CrossRef]
  59. Drabek, T.; Kochanek, P.M.; Stezoski, J.; Wu, X.; Bayir, H.; Morhard, R.C.; Stezoski, S.W.; Tisherman, S.A. Intravenous hydrogen sulfide does not induce hypothermia or improve survival from hemorrhagic shock in pigs. Shock 2011, 35, 67–73. [Google Scholar] [CrossRef]
  60. Szabo, C. Gaseotransmitters: New frontiers for translational science. Sci. Transl. Med. 2010, 2, 59ps54. [Google Scholar] [CrossRef] [Green Version]
  61. Gutkowska, J.; Jankowski, M.; Antunes-Rodrigues, J. The role of oxytocin in cardiovascular regulation. Braz. J. Med. Biol. Res. 2014, 47, 206–214. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Gutkowska, J.; Jankowski, M.; Lambert, C.; Mukaddam-Daher, S.; Zingg, H.H.; McCann, S.M. Oxytocin releases atrial natriuretic peptide by combining with oxytocin receptors in the heart. Proc. Natl. Acad. Sci. USA 1997, 94, 11704–11709. [Google Scholar] [CrossRef] [Green Version]
  63. Jankowski, M.; Hajjar, F.; Kawas, S.A.; Mukaddam-Daher, S.; Hoffman, G.; McCann, S.M.; Gutkowska, J. Rat heart: A site of oxytocin production and action. Proc. Natl. Acad. Sci. USA 1998, 95, 14558–14563. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Jankowski, M.; Wang, D.; Hajjar, F.; Mukaddam-Daher, S.; McCann, S.M.; Gutkowska, J. Oxytocin and its receptors are synthesized in the rat vasculature. Proc. Natl. Acad. Sci. USA 2000, 97, 6207–6211. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Szeto, A.; Sun-Suslow, N.; Mendez, A.J.; Hernandez, R.I.; Wagner, K.V.; McCabe, P.M. Regulation of the macrophage oxytocin receptor in response to inflammation. Am. J. Physiol. Endocrinol. Metab. 2017, 312, E183–E189. [Google Scholar] [CrossRef] [PubMed]
  66. Krause, S.; Boeck, C.; Gumpp, A.M.; Rottler, E.; Schury, K.; Karabatsiakis, A.; Buchheim, A.; Gündel, H.; Kolassa, I.T.; Waller, C. Child Maltreatment Is Associated with a Reduction of the Oxytocin Receptor in Peripheral Blood Mononuclear Cells. Front. Psychol. 2018, 9, 173. [Google Scholar] [CrossRef] [Green Version]
  67. Ali, I.I.; Al-Salam, S.; Howarth, F.C.; Shmygol, A. Oxytocin induces intracellular Ca2+ release in cardiac fibroblasts from neonatal rats. Cell Calcium. 2019, 84, 102099. [Google Scholar] [CrossRef]
  68. Jankowski, M.; Broderick, T.L.; Gutkowska, J. Oxytocin and cardioprotection in diabetes and obesity. BMC Endocr. Disord. 2016, 16, 34. [Google Scholar] [CrossRef] [Green Version]
  69. Faghihi, M.; Alizadeh, A.M.; Khori, V.; Latifpour, M.; Khodayari, S. The role of nitric oxide, reactive oxygen species, and protein kinase C in oxytocin-induced cardioprotection in ischemic rat heart. Peptides 2012, 37, 314–319. [Google Scholar] [CrossRef]
  70. Gutkowska, J.; Jankowski, M. Oxytocin revisited: Its role in cardiovascular regulation. J. Neuroendocr. 2012, 24, 599–608. [Google Scholar] [CrossRef]
  71. Kajstura, J.; Hosoda, T.; Bearzi, C.; Rota, M.; Maestroni, S.; Urbanek, K.; Leri, A.; Anversa, P. The human heart: A self-renewing organ. Clin. Transl. Sci. 2008, 1, 80–86. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Mukaddam-Daher, S.; Yin, Y.L.; Roy, J.; Gutkowska, J.; Cardinal, R. Negative inotropic and chronotropic effects of oxytocin. Hypertension 2001, 38, 292–296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Holst, S.; Uvnas-Moberg, K.; Petersson, M. Postnatal oxytocin treatment and postnatal stroking of rats reduce blood pressure in adulthood. Auton. Neurosci. 2002, 99, 85–90. [Google Scholar] [CrossRef]
  74. Petersson, M.; Uvnas-Moberg, K. Postnatal oxytocin treatment of spontaneously hypertensive male rats decreases blood pressure and body weight in adulthood. Neurosci. Lett. 2008, 440, 166–169. [Google Scholar] [CrossRef]
  75. Całka, J. The role of nitric oxide in the hypothalamic control of LHRH and oxytocin release, sexual behavior and aging of the LHRH and oxytocin neurons. Folia. Histochem. Cytobiol. 2006, 44, 3–12. [Google Scholar] [CrossRef]
  76. Correa, P.B.; Pancoto, J.A.; Oliveira-Pelegrin, G.R.; Carnio, E.C.; Rocha, M.J. Participation of iNOS-derived NO in hypothalamic activation and vasopressin release during polymicrobial sepsis. J. Neuroimmunol. 2007, 183, 17–25. [Google Scholar] [CrossRef]
  77. Kadekaro, M.; Summy-Long, J.Y. Centrally produced nitric oxide and the regulation of body fluid and blood pressure homeostases. Clin. Exp. Pharm. Physiol. 2000, 27, 450–459. [Google Scholar] [CrossRef]
  78. Reis, W.L.; Giusti-Paiva, A.; Ventura, R.R.; Margatho, L.O.; Gomes, D.A.; Elias, L.L.; Antunes-Rodrigues, J. Central nitric oxide blocks vasopressin, oxytocin and atrial natriuretic peptide release and antidiuretic and natriuretic responses induced by central angiotensin II in conscious rats. Exp. Physiol. 2007, 92, 903–911. [Google Scholar] [CrossRef]
  79. Alizadeh, A.M.; Faghihi, M.; Sadeghipour, H.R.; Mohammadghasemi, F.; Khori, V. Role of endogenous oxytocin in cardiac ischemic preconditioning. Regul. Pept. 2011, 167, 86–90. [Google Scholar] [CrossRef] [Green Version]
  80. Jankowski, M.; Bissonauth, V.; Gao, L.; Gangal, M.; Wang, D.; Danalache, B.; Wang, Y.; Stoyanova, E.; Cloutier, G.; Blaise, G.; et al. Anti-inflammatory effect of oxytocin in rat myocardial infarction. Basic. Res. Cardiol. 2010, 105, 205–218. [Google Scholar] [CrossRef]
  81. Moghimian, M.; Faghihi, M.; Karimian, S.M.; Imani, A.; Houshmand, F.; Azizi, Y. Role of central oxytocin in stress-induced cardioprotection in ischemic-reperfused heart model. J. Cardiol. 2013, 61, 79–86. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Ondrejcakova, M.; Barancik, M.; Bartekova, M.; Ravingerova, T.; Jezova, D. Prolonged oxytocin treatment in rats affects intracellular signaling and induces myocardial protection against infarction. Gen. Physiol. Biophys. 2012, 31, 261–270. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Gutkowska, J.; Broderick, T.L.; Bogdan, D.; Wang, D.; Lavoie, J.M.; Jankowski, M. Downregulation of oxytocin and natriuretic peptides in diabetes: Possible implications in cardiomyopathy. J. Physiol. 2009, 587, 4725–4736. [Google Scholar] [CrossRef]
  84. Broderick, T.L.; Wang, Y.; Gutkowska, J.; Wang, D.; Jankowski, M. Downregulation of oxytocin receptors in right ventricle of rats with monocrotaline-induced pulmonary hypertension. Acta Physiol. 2010, 200, 147–158. [Google Scholar] [CrossRef] [PubMed]
  85. Authier, S.; Tanguay, J.F.; Geoffroy, P.; Gauvin, D.; Bichot, S.; Ybarra, N.; Otis, C.; Troncy, E. Cardiovascular effects of oxytocin infusion in a porcine model of myocardial infarct. J. Cardiovasc. Pharm. 2010, 55, 74–82. [Google Scholar] [CrossRef] [PubMed]
  86. Mani, S.; Li, H.; Untereiner, A.; Wu, L.; Yang, G.; Austin, R.C.; Dickhout, J.G.; Lhoták, Š.; Meng, Q.H.; Wang, R. Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. Circulation 2013, 127, 2523–2534. [Google Scholar] [CrossRef] [Green Version]
  87. Wang, Y.; Zhao, X.; Jin, H.; Wei, H.; Li, W.; Bu, D.; Tang, X.; Ren, Y.; Tang, C.; Du, J. Role of hydrogen sulfide in the development of atherosclerotic lesions in apolipoprotein E knockout mice. Arter. Thromb. Vasc. Biol. 2009, 29, 173–179. [Google Scholar] [CrossRef]
  88. Ahmed, M.A.; ELosaily, G.M. Role of Oxytocin in deceleration of early atherosclerotic inflammatory processes in adult male rats. Int. J. Clin. Exp. Med. 2011, 4, 169–178. [Google Scholar] [CrossRef] [Green Version]
  89. Szeto, A.; Rossetti, M.A.; Mendez, A.J.; Noller, C.M.; Herderick, E.E.; Gonzales, J.A.; Schneiderman, N.; McCabe, P.M. Oxytocin administration attenuates atherosclerosis and inflammation in Watanabe Heritable Hyperlipidemic rabbits. Psychoneuroendocrinology 2013, 38, 685–693. [Google Scholar] [CrossRef] [Green Version]
  90. Matějková, Š.; Scheuerle, A.; Wagner, F.; McCook, O.; Matallo, J.; Gröger, M.; Seifritz, A.; Stahl, B.; Vcelar, B.; Calzia, E.; et al. Carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine kidney ischemia/reperfusion injury. Intensive Care Med. 2013, 39, 497–510. [Google Scholar] [CrossRef]
  91. Thim, T.; Hagensen, M.K.; Drouet, L.; Sollier, C.B.D.; Bonneau, M.; Granada, J.F.; Nielsen, L.B.; Paaske, W.P.; Bøtker, H.E.; Falk, E. Familial hypercholesterolaemic downsized pig with human-like coronary atherosclerosis: A model for preclinical studies. Eurointervention 2010, 6, 261–268. [Google Scholar] [CrossRef] [PubMed]
  92. Jin, S.; Teng, X.; Xiao, L.; Xue, H.; Guo, Q.; Duan, X.; Chen, Y.; Wu, Y. Hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease by the Akt/eNOS/NO pathway. Exp. Biol. Med. 2017, 242, 1831–1841. [Google Scholar] [CrossRef] [PubMed]
  93. Singh, S.; Sharma, R.; Kumari, M.; Tiwari, S. Insulin receptors in the kidneys in health and disease. World J. Nephrol. 2019, 8, 11–22. [Google Scholar] [CrossRef]
  94. Elabd, S.; Sabry, I. Two Birds with One Stone: Possible Dual-Role of Oxytocin in the Treatment of Diabetes and Osteoporosis. Front. Endocrinol. 2015, 6, 121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Untereiner, A.; Wu, L. Hydrogen Sulfide and Glucose Homeostasis: A Tale of Sweet and the Stink. Antioxid Redox Signal. 2018, 28, 1463–1482. [Google Scholar] [CrossRef] [PubMed]
  96. Florian, M.; Jankowski, M.; Gutkowska, J. Oxytocin increases glucose uptake in neonatal rat cardiomyocytes. Endocrinology 2010, 151, 482–491. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Zhang, H.; Huang, Y.; Chen, S.; Tang, C.; Wang, G.; Du, J.; Jin, H. Hydrogen sulfide regulates insulin secretion and insulin resistance in diabetes mellitus, a new promising target for diabetes mellitus treatment? A review. J. Adv. Res. 2020. [Google Scholar] [CrossRef]
  98. Gajdosechova, L.; Krskova, K.; Segarra, A.B.; Spolcova, A.; Suski, M.; Olszanecki, R.; Zorad, S. Hypooxytocinaemia in obese Zucker rats relates to oxytocin degradation in liver and adipose tissue. J. Endocrinol. 2014, 220, 333–343. [Google Scholar] [CrossRef] [Green Version]
  99. Merz, T.; Vogt, J.A.; Wachter, U.; Calzia, E.; Szabo, C.; Wang, R.; Radermacher, P.; McCook, O. Impact of hyperglycemia on cystathionine-γ-lyase expression during resuscitated murine septic shock. Intensive Care Med. Exp. 2017, 5, 30. [Google Scholar] [CrossRef]
  100. Widmaier, E.P.; Shah, P.R.; Lee, G. Interactions between oxytocin, glucagon and glucose in normal and streptozotocin-induced diabetic rats. Regul. Pept. 1991, 34, 235–249. [Google Scholar] [CrossRef]
  101. Balint, E.M.; Boseva, P.; Schury, K.; Guendel, H.; Rottbauer, W.; Waller, C. High prevalence of posttraumatic stress in patients with primary hypertension. Gen. Hosp. Psychiatry 2016, 38, 53–58. [Google Scholar] [CrossRef] [PubMed]
  102. Felitti, V.J.; Anda, R.F.; Nordenberg, D.; Williamson, D.F.; Spitz, A.M.; Edwards, V.; Koss, M.P.; Marks, J.S. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am. J. Prev. Med. 1998, 14, 245–258. [Google Scholar] [CrossRef]
  103. Loria, A.S.; Ho, D.H.; Pollock, J.S. A mechanistic look at the effects of adversity early in life on cardiovascular disease risk during adulthood. Acta Physiol. 2014, 210, 277–287. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Van der Kooy, K.; Van Hout, H.; Marwijk, H.; Marten, H.; Stehouwer, C.; Beekman, A. Depression and the risk for cardiovascular diseases: Systematic review and meta analysis. Int. J. Geriatr. Psychiatry 2007, 22, 613–626. [Google Scholar] [CrossRef] [PubMed]
  105. Ma, Y.; Li, S.; Wang, C.; Liu, Y.; Li, W.; Yan, X.; Chen, Q.; Han, S. Distinct oxytocin effects on belief updating in response to desirable and undesirable feedback. Proc. Natl. Acad. Sci. USA 2016, 113, 9256–9261. [Google Scholar] [CrossRef] [Green Version]
  106. Saphire-Bernstein, S.; Way, B.M.; Kim, H.S.; Sherman, D.K.; Taylor, S.E. Oxytocin receptor gene (OXTR) is related to psychological resources. Proc. Natl. Acad. Sci. USA 2011, 108, 15118–15122. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Dobruch, J.; Cudnoch-Jedrzejewska, A.; Szczepanska-Sadowska, E. Enhanced involment of brain vasopressin V1 receptors in cardiovascular responses to stress in rats with myocardial infarction. Stress 2005, 8, 273–284. [Google Scholar] [CrossRef]
  108. Fleet, R.; Lesperance, F.; Arsenault, A.; Gregoire, J.; Lavoie, K.; Laurin, C.; Harel, F.; Burelle, D.; Lambert, J.; Beitman, B.; et al. Myocardial perfusion study of panic attacks in patients with coronary artery disease. Am. J. Cardiol. 2005, 96, 1064–1068. [Google Scholar] [CrossRef]
  109. Peters, S.; Slattery, D.A.; Uschold-Schmidt, N.; Reber, S.O.; Neumann, I.D. Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice. Psychoneuroendocrinology 2014, 42, 225–236. [Google Scholar] [CrossRef]
  110. Wsol, A.; Cudnoch-Jedrzejewska, A.; Szczepanska-Sadowska, E.; Kowalewski, S.; Puchalska, L. Oxytocin in the cardiovascular responses to stress. J. Physiol. Pharm. 2008, 59, 123–127. [Google Scholar]
  111. Callahan, M.F.; Kirby, R.F.; Cunningham, J.T.; Eskridge-Sloop, S.L.; Johnson, A.K.; McCarty, R.; Gruber, K.A. Central oxytocin systems may mediate a cardiovascular response to acute stress in rats. Am. J. Physiol. 1989, 256, H1369–H1377. [Google Scholar] [CrossRef] [PubMed]
  112. Grewen, K.M.; Light, K.C. Plasma oxytocin is related to lower cardiovascular and sympathetic reactivity to stress. Biol. Psychol. 2011, 87, 340–349. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Wigger, D.C.; Gröger, N.; Lesse, A.; Krause, S.; Merz, T.; Gündel, H.; Braun, K.; McCook, O.; Radermacher, P.; Bock, J.; et al. Maternal Separation Induces Long-Term Alterations in the Cardiac Oxytocin Receptor and Cystathionine γ-Lyase Expression in Mice. Oxid. Med. Cell Longev. 2020, 4309605. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Li, B.; Lee, C.; Martin, Z.; Li, X.; Koike, Y.; Hock, A.; Zani-Ruttenstock, E.; Zani, A.; Pierro, A. Intestinal epithelial injury induced by maternal separation is protected by hydrogen sulfide. J. Pediatr. Surg. 2016, 52, 40–44. [Google Scholar] [CrossRef]
  115. Iseri, S.O.; Sener, G.; Saglam, B.; Gedik, N.; Ercan, F.; Yegen, B.C. Oxytocin ameliorates oxidative colonic inflammation by a neutrophil-dependent mechanism. Peptides 2005, 26, 483–491. [Google Scholar] [CrossRef]
  116. Szabo, C.; Papapetropoulos, A. International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors. Pharm. Rev. 2017, 69, 497–564. [Google Scholar] [CrossRef] [Green Version]
  117. Merz, T.; Denoix, N.; Wepler, M.; Gäßler, H.; Messerer, D.A.C.; Hartmann, C.; Datzmann, T.; Radermacher, P.; McCook, O. H2S in acute lung injury: A therapeutic dead end(?). Intensive Care Med. Exp. 2020, in press. [Google Scholar]
  118. Buemann, B.; Uvnäs-Moberg, K. Oxytocin may have a therapeutical potential against cardiovascular disease. Possible pharmaceutical and behavioral approaches. Med. Hypotheses 2020, 138, 109597. [Google Scholar] [CrossRef]
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Figure 1. H2S biosynthesis and oxidation pathways. H2S can be produced in the vasculature, heart, brain, placenta, colonic tissue, liver, kidney and other mammalian tissues [8]. L-cysteine and homocysteine are the essential substrates for enzymatic endogenous H2S production by CSE, CBS or 3MST. L-Cysteine can be directly used as a substrate for H2S generation via the enzymes CSE or CBS. Homocysteine is converted to cystathionine by CBS and then converted to H2S by CSE. Cysteine-aminotransferase (CAT) can metabolize L-cysteine to 3-mercaptopyruvate, which is then converted to H2S by 3MST. CSE, CBS and CAT require the cofactor pyridoxal 5′-phosphate (PLP) [8]. Non-enzymatic H2S generation can take place during hypoxic events, for example, via thiosulfate utilization. Thiosulfate is an oxidation product of H2S, which is part of the stepwise enzymatic sulfide oxidation pathway within the mitochondria and can be reduced, e.g., with glutathione (GSH), to H2S [8,9]. Sulfide quinone oxidoreductase (SQR) oxidizes H2S to glutathione persulfide (GSSH); that is followed by oxidation of GSSH to sulfite by persulfide dioxygenase (SDO); and finally, sulfite is oxidized to either sulfate by sulfite oxidase (SO) or to thiosulfate by rhodanese.
Figure 1. H2S biosynthesis and oxidation pathways. H2S can be produced in the vasculature, heart, brain, placenta, colonic tissue, liver, kidney and other mammalian tissues [8]. L-cysteine and homocysteine are the essential substrates for enzymatic endogenous H2S production by CSE, CBS or 3MST. L-Cysteine can be directly used as a substrate for H2S generation via the enzymes CSE or CBS. Homocysteine is converted to cystathionine by CBS and then converted to H2S by CSE. Cysteine-aminotransferase (CAT) can metabolize L-cysteine to 3-mercaptopyruvate, which is then converted to H2S by 3MST. CSE, CBS and CAT require the cofactor pyridoxal 5′-phosphate (PLP) [8]. Non-enzymatic H2S generation can take place during hypoxic events, for example, via thiosulfate utilization. Thiosulfate is an oxidation product of H2S, which is part of the stepwise enzymatic sulfide oxidation pathway within the mitochondria and can be reduced, e.g., with glutathione (GSH), to H2S [8,9]. Sulfide quinone oxidoreductase (SQR) oxidizes H2S to glutathione persulfide (GSSH); that is followed by oxidation of GSSH to sulfite by persulfide dioxygenase (SDO); and finally, sulfite is oxidized to either sulfate by sulfite oxidase (SO) or to thiosulfate by rhodanese.
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Figure 2. H2S can stimulate hypothalamic OT release. (A): OT, OTR, CSE and CBS co-localize (in red) in the magnocellular neurons (open arrow heads) of the porcine hypothalamus. Black arrows are pointing to the same blood vessel in consecutive brain sections of the porcine hypothalamus (10×). Brain sections were obtained from an atherosclerotic pig model of resuscitated hemorrhagic shock [27]. Hypothalamic immunohistochemical pictures have been previously published in an abstract in: 39th International Symposium on Intensive Care and Emergency Medicine. Crit Care 23, 72 (2019). https://doi.org/10.1186/s13054-019-2358-0 (http://creativecommons.org/licenses/by/4.0/). The used antibodies have been verified for their specificity previously by Denoix et al. [25]. (B): H2S can stimulate OT release in the hypothalamus, including the PVN and SON, in response to osmotic balance stress and fluid shifts. H2S is endogenously enzymatically produced by CSE, CBS and 3MST. Hypothalamic OT is released via the posterior pituitary into the circulation, where it contributes to the maintenance of cardiovascular homeostasis. Illustrations of the heart, brain, neurons and the circulatory system were taken from the Library of Science and Medical lllustrations (somersault18:24, https://creativecommons.org/licenses/by-nc-sa/4.0/).
Figure 2. H2S can stimulate hypothalamic OT release. (A): OT, OTR, CSE and CBS co-localize (in red) in the magnocellular neurons (open arrow heads) of the porcine hypothalamus. Black arrows are pointing to the same blood vessel in consecutive brain sections of the porcine hypothalamus (10×). Brain sections were obtained from an atherosclerotic pig model of resuscitated hemorrhagic shock [27]. Hypothalamic immunohistochemical pictures have been previously published in an abstract in: 39th International Symposium on Intensive Care and Emergency Medicine. Crit Care 23, 72 (2019). https://doi.org/10.1186/s13054-019-2358-0 (http://creativecommons.org/licenses/by/4.0/). The used antibodies have been verified for their specificity previously by Denoix et al. [25]. (B): H2S can stimulate OT release in the hypothalamus, including the PVN and SON, in response to osmotic balance stress and fluid shifts. H2S is endogenously enzymatically produced by CSE, CBS and 3MST. Hypothalamic OT is released via the posterior pituitary into the circulation, where it contributes to the maintenance of cardiovascular homeostasis. Illustrations of the heart, brain, neurons and the circulatory system were taken from the Library of Science and Medical lllustrations (somersault18:24, https://creativecommons.org/licenses/by-nc-sa/4.0/).
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Figure 3. Interaction of H2S and OT in the heart. (A): Immunohistochemical staining of OTR in heart tissue in a CSEko heart (n = 3, top) and a wild-type heart (n = 3, bottom). Heart samples were obtained from naïve animals, which were anesthetized with sevoflurane and buprenorphine and sacrificed via exsanguination (as previously described in [19]). Expression of OTR was absent in CSEko heart and clearly visible in wild-type myocardial tissue. (B): The physiological basis of the interaction of CSE and the OTR, converging in the reperfusion injury salvage kinase (RISK) pathway. H2S, mainly produced by CSE in the cardiovascular system, and the OTR, stimulated by OT, can both activate the RISK pathway. RISK activation leads to PI3K, protein kinase B (Akt), ERK1/2 cascades and endothelial nitric oxide synthase (eNOS) activation, and promotes reperfusion by stimulating cell migration, angiogenesis and vasodilation, resulting in cardio-protection, regulation of blood pressure, blood volume and body fluid homeostasis. The illustration of the heart was taken from the Library of Science and Medical Illustrations (somersault18:24, https://creativecommons.org/licenses/by-nc-sa/4.0/).
Figure 3. Interaction of H2S and OT in the heart. (A): Immunohistochemical staining of OTR in heart tissue in a CSEko heart (n = 3, top) and a wild-type heart (n = 3, bottom). Heart samples were obtained from naïve animals, which were anesthetized with sevoflurane and buprenorphine and sacrificed via exsanguination (as previously described in [19]). Expression of OTR was absent in CSEko heart and clearly visible in wild-type myocardial tissue. (B): The physiological basis of the interaction of CSE and the OTR, converging in the reperfusion injury salvage kinase (RISK) pathway. H2S, mainly produced by CSE in the cardiovascular system, and the OTR, stimulated by OT, can both activate the RISK pathway. RISK activation leads to PI3K, protein kinase B (Akt), ERK1/2 cascades and endothelial nitric oxide synthase (eNOS) activation, and promotes reperfusion by stimulating cell migration, angiogenesis and vasodilation, resulting in cardio-protection, regulation of blood pressure, blood volume and body fluid homeostasis. The illustration of the heart was taken from the Library of Science and Medical Illustrations (somersault18:24, https://creativecommons.org/licenses/by-nc-sa/4.0/).
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MDPI and ACS Style

Denoix, N.; McCook, O.; Ecker, S.; Wang, R.; Waller, C.; Radermacher, P.; Merz, T. The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System. Antioxidants 2020, 9, 748. https://doi.org/10.3390/antiox9080748

AMA Style

Denoix N, McCook O, Ecker S, Wang R, Waller C, Radermacher P, Merz T. The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System. Antioxidants. 2020; 9(8):748. https://doi.org/10.3390/antiox9080748

Chicago/Turabian Style

Denoix, Nicole, Oscar McCook, Sarah Ecker, Rui Wang, Christiane Waller, Peter Radermacher, and Tamara Merz. 2020. "The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System" Antioxidants 9, no. 8: 748. https://doi.org/10.3390/antiox9080748

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