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Molecular Interactions of Arterial Hypertension in Its Target Organs

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 20335

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Prof. Dr. Joaquín García-Estañ

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Depto. Fisiología, Universidad de Murcia, Murcia, Spain
Interests: kidney; nitric oxide; calcium signaling
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Felix Vargas

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Depto. Fisiología, Universidad de Granada, Granada, Spain
Interests: kidney; aminopeptidases; arterial hypertension; nitric oxide
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Rosemary Wangensteen

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Depto. Fisiología, Universidad de Jaén, Jaén, Spain
Interests: Kidney Health and Disease; aminopeptidases; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Arterial hypertension is a condition of persistent, abnormal elevation of systemic arterial or blood pressure. Hypertension affects a substantial proportion of the adult population worldwide. Numerous genetic, environmental, and behavioral factors influence the development of hypertension. In turn, hypertension has been identified as a major causative risk factor for cardiovascular disease, including heart and kidney disease, peripheral vascular disease, and stroke. For the present Special Issue, we would like to receive papers, either experimental studies or reviews, that explore the multiple molecular mechanisms that have a role in the damage to target organs, including heart, kidney, brain, retina, and blood vessels. In addition, a variety of cells, molecules, and cytokines are involved in the whole process, and thus it is very important to study their interactions and mechanisms. Moreover, the effects that the antihypertensive treatments and their mechanisms exert on these biological components are also worth analyzing.

Prof. Dr. Joaquín García-Estañ
Prof. Dr. Felix Vargas
Prof. Dr. Rosemary Wangensteen
Guest Editors

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Keywords

Angiotensin II
Antihypertensive agents
Blood pressure
Blood vessels
Bradykinin
Catecholamines
Central nervous system
Genetics
End-organ damage
Endothelial dysfunction
Endothelin
Flavonoids
Inflammation
Kidney
Microbiota
Immune system
Nitric oxide
Physiology
Physiopathology
Renin–angiotensin–aldosterone system
Reactive oxygen species
Retinopathy
Stroke
Sympathetic nervous system
Vasopressin

Published Papers (7 papers)

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Research

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14 pages, 3936 KiB

Open AccessArticle

Angiotensin Type 2 and Mas Receptor Activation Prevents Myocardial Fibrosis and Hypertrophy through the Reduction of Inflammatory Cell Infiltration and Local Sympathetic Activity in Angiotensin II-Dependent Hypertension

by Giovanna Castoldi, Raffaella Carletti, Silvia Ippolito, Andrea Stella, Gianpaolo Zerbini, Sara Pelucchi, Giovanni Zatti and Cira R. T. di Gioia

Int. J. Mol. Sci. 2021, 22(24), 13678; https://doi.org/10.3390/ijms222413678 - 20 Dec 2021

Cited by 16 | Viewed by 2894

Abstract

Compound 21 (C21), an AT2 receptor agonist, and Angiotensin 1-7 (Ang 1-7), through Mas receptor, play an important role in the modulation of the protective arm of the renin-angiotensin system. The aim of this study was to investigate in an experimental model of angiotensin II-dependent hypertension whether the activation of the potentially protective arm of the renin-angiotensin system, through AT2 or Mas receptor stimulation, counteracts the onset of myocardial fibrosis and hypertrophy, and whether these effects are mediated by inflammatory mechanism and/or sympathetic activation. Sprague Dawley rats (n = 67) were treated for 1 (n = 25) and 4 (n = 42) weeks and divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis); (b) Ang II+Compound 21 (C21, 0.3 mg/kg/day, intraperitoneal); (c) Ang II+Ang 1-7 (576 µg/kg/day, intraperitoneal); (d) Ang II+Losartan (50 mg/kg/day, per os); (e) control group (physiological saline, sub cutis). Systolic blood pressure was measured by tail cuff method and, at the end of the experimental period, the rats were euthanized and the heart was excised to evaluate myocardial fibrosis, hypertrophy, inflammatory cell infiltration and tyrosine hydroxylase expression, used as marker of sympathetic activity. Ang II caused a significant increase of blood pressure, myocardial interstitial and perivascular fibrosis and myocardial hypertrophy, as compared to control groups. C21 or Ang 1-7 administration did not modify the increase in blood pressure in Ang II treated rats, but both prevented the development of myocardial fibrosis and hypertrophy. Treatment with losartan blocked the onset of hypertension and myocardial fibrosis and hypertrophy in Ang II treated rats. Activation of AT2 receptors or Mas receptors prevents the onset of myocardial fibrosis and hypertrophy in Ang II-dependent hypertension through the reduction of myocardial inflammatory cell infiltration and tyrosine hydroxylase expression. Unlike what happens in case of treatment with losartan, the antifibrotic and antihypertrophic effects that follow the activation of the AT2 or Mas receptors are independent on the modulation of blood pressure. Full article

(This article belongs to the Special Issue Molecular Interactions of Arterial Hypertension in Its Target Organs)

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30 pages, 11220 KiB

Open AccessArticle

Stearoyl-CoA Desaturase (SCD) Induces Cardiac Dysfunction with Cardiac Lipid Overload and Angiotensin II AT1 Receptor Protein Up-Regulation

by Joshua Abd Alla, Yahya F. Jamous and Ursula Quitterer

Int. J. Mol. Sci. 2021, 22(18), 9883; https://doi.org/10.3390/ijms22189883 - 13 Sep 2021

Cited by 5 | Viewed by 2511

Abstract

Heart failure is a major cause of death worldwide with insufficient treatment options. In the search for pathomechanisms, we found up-regulation of an enzyme, stearoyl-CoA desaturase 1 (Scd1), in different experimental models of heart failure induced by advanced atherosclerosis, chronic pressure overload, and/or volume overload. Because the pathophysiological role of Scd1/SCD in heart failure is not clear, we investigated the impact of cardiac SCD upregulation through the generation of C57BL/6-Tg(MHCSCD)Sjaa mice with myocardium-specific expression of SCD. Echocardiographic examination showed that 4.9-fold-increased SCD levels triggered cardiac hypertrophy and symptoms of heart failure at an age of eight months. Tg-SCD mice had a significantly reduced left ventricular cardiac ejection fraction of 25.7 ± 2.9% compared to 54.3 ± 4.5% of non-transgenic B6 control mice. Whole-genome gene expression profiling identified up-regulated heart-failure-related genes such as resistin, adiponectin, and fatty acid synthase, and type 1 and 3 collagens. Tg-SCD mice were characterized by cardiac lipid accumulation with 1.6- and 1.7-fold-increased cardiac contents of saturated lipids, palmitate, and stearate, respectively. In contrast, unsaturated lipids were not changed. Together with saturated lipids, apoptosis-enhancing p53 protein contents were elevated. Imaging by autoradiography revealed that the heart-failure-promoting and membrane-spanning angiotensin II AT1 receptor protein of Tg-SCD hearts was significantly up-regulated. In transfected HEK cells, the expression of SCD increased the number of cell-surface angiotensin II AT1 receptor binding sites. In addition, increased AT1 receptor protein levels were detected by fluorescence spectroscopy of fluorescent protein-labeled AT1 receptor-Cerulean. Taken together, we found that SCD promotes cardiac dysfunction with overload of cardiotoxic saturated lipids and up-regulation of the heart-failure-promoting AT1 receptor protein. Full article

(This article belongs to the Special Issue Molecular Interactions of Arterial Hypertension in Its Target Organs)

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14 pages, 2812 KiB

Open AccessArticle

Proanthocyanidins Maintain Cardiac Ionic Homeostasis in Aldosterone-Induced Hypertension and Heart Failure

by Natalia de las Heras, Adrián Galiana, Sandra Ballesteros, Elena Olivares-Álvaro, Peter J. Fuller, Vicente Lahera and Beatriz Martín-Fernández

Int. J. Mol. Sci. 2021, 22(17), 9602; https://doi.org/10.3390/ijms22179602 - 04 Sep 2021

Cited by 4 | Viewed by 2408

Abstract

Excess aldosterone promotes pathological remodeling of the heart and imbalance in cardiac ion homeostasis of sodium, potassium and calcium. Novel treatment with proanthocyanidins in aldosterone-treated rats has resulted in downregulation of cardiac SGK1, the main genomic aldosterone-induced intracellular mediator of ion handling. It therefore follows that proanthocyanidins could be modulating cardiac ion homeostasis in aldosterone-treated rats. Male Wistar rats received aldosterone (1 mg kg⁻¹ day⁻¹) +1% NaCl for three weeks. Half of the animals in each group were simultaneously treated with the proanthocyanidins-rich extract (80% w/w) (PRO80, 5 mg kg⁻¹ day⁻¹). PRO80 prevented cardiac hypertrophy and decreased calcium content. Expression of ion channels (ROMK, NHE1, NKA and NCX1) and calcium transient mediators (CAV1.2, pCaMKII and oxCaMKII) were reduced by PRO80 treatment in aldosterone-treated rats. To conclude, our data indicate that PRO80 may offer an alternative treatment to conventional MR-blockade in the prevention of aldosterone-induced cardiac pathology. Full article

(This article belongs to the Special Issue Molecular Interactions of Arterial Hypertension in Its Target Organs)

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12 pages, 2522 KiB

Open AccessArticle

Interaction between Angiotensinase Activities in Pituitary and Adrenal Glands of Wistar–Kyoto and Spontaneously Hypertensive Rats under Hypotensive or Hypertensive Treatments

by Ana B. Segarra, Isabel Prieto, Inmaculada Banegas, Magdalena Martínez-Cañamero, Ana B. Villarejo, Germán Domínguez-Vías, Marc de Gasparo and Manuel Ramírez-Sánchez

Int. J. Mol. Sci. 2021, 22(15), 7823; https://doi.org/10.3390/ijms22157823 - 22 Jul 2021

Cited by 3 | Viewed by 1588

Abstract

In the present study, we analyzed the activity of several aminopeptidases (angiotensinases) involved in the metabolism of various angiotensin peptides, in pituitary and adrenal glands of untreated Wistar–Kyoto (WKY) and spontaneously hypertensive rats (SHR) or treated with the antihypertensive drugs captopril and propranolol or with the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). Intra- and inter-gland correlations between angiotensinase activities were also calculated. Membrane-bound alanyl-, cystinyl-, and glutamyl-aminopeptidase activities were determined fluorometrically using aminoacyl-β-naphthylamide as substrates. Depending on the type of angiotensinase analyzed, the results reflect a complex picture showing substantial differences between glands, strains, and treatments. Alanyl-aminopeptidase responsible for the metabolism of Ang III to Ang IV appears to be the most active angiotensinase in both pituitary and adrenals of WKY and particularly in SHR. Independently of treatment, most positive correlations are observed in the pituitary gland of WKY whereas such positive correlations are predominant in adrenals of SHR. Negative inter-gland correlations were observed in control SHR and L-NAME treated WKY. Positive inter-gland correlations were observed in captopril-treated SHR and propranolol-treated WKY. These results may reflect additional mechanisms for increasing or decreasing systolic blood pressure in WKY or SHR. Full article

(This article belongs to the Special Issue Molecular Interactions of Arterial Hypertension in Its Target Organs)

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14 pages, 1069 KiB

Open AccessArticle

Effects of Virgin Olive Oil on Blood Pressure and Renal Aminopeptidase Activities in Male Wistar Rats

by Germán Domínguez-Vías, Ana Belén Segarra, Manuel Ramírez-Sánchez and Isabel Prieto

Int. J. Mol. Sci. 2021, 22(10), 5388; https://doi.org/10.3390/ijms22105388 - 20 May 2021

Cited by 7 | Viewed by 3275

Abstract

High saturated fat diets have been associated with the development of obesity and hypertension, along with other pathologies related to the metabolic syndrome. In contrast, the Mediterranean diet, characterized by its high content of monounsaturated fatty acids, has been proposed as a dietary factor capable of positively regulating cardiovascular function. These effects have been linked to changes in the local renal renin angiotensin system (RAS) and the activity of the sympathetic nervous system. The main goal of this study was to analyze the role of two dietary fat sources on aminopeptidases activities involved in local kidney RAS. Male Wistar rats (six months old) were fed during 24 weeks with three different diets: the standard diet (S), the standard diet supplemented with virgin olive oil (20%) (VOO), or the standard diet enriched with butter (20%) plus cholesterol (0.1%) (Bch). Kidney samples were separated in medulla and cortex for aminopeptidase activities (AP) assay. Urine samples were collected for routine analysis by chemical tests. Aminopeptidase activities were determined by fluorometric methods in soluble (sol) and membrane-bound (mb) fractions of renal tissue, using arylamide derivatives as substrates. After the experimental period, the systolic blood pressure (SBP) values were similar in standard and VOO animals, and significantly lower than in the Bch group. At the same time, a significant increase in GluAP and IRAP activities were found in renal medulla of Bch animals. However, in VOO group the increase of GluAP activity in renal medulla was lower, while AspAP activity decreased in the renal cortex. Furthermore, the VOO diet also affected other aminopeptidase activities, such as TyrAP and pGluAP, related to the regulation of the sympathetic nervous system and the metabolic rate. These results support the beneficial effect of VOO in the regulation of SBP through changes in local AP activities of the kidney. Full article

(This article belongs to the Special Issue Molecular Interactions of Arterial Hypertension in Its Target Organs)

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21 pages, 3171 KiB

Open AccessArticle

Beneficial Changes in Rat Vascular Endocannabinoid System in Primary Hypertension and under Treatment with Chronic Inhibition of Fatty Acid Amide Hydrolase by URB597

by Marta Baranowska-Kuczko, Hanna Kozłowska, Monika Kloza, Ewa Harasim-Symbor, Michał Biernacki, Irena Kasacka and Barbara Malinowska

Int. J. Mol. Sci. 2021, 22(9), 4833; https://doi.org/10.3390/ijms22094833 - 02 May 2021

Cited by 9 | Viewed by 2361

Abstract

Our study aimed to examine the effects of hypertension and the chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on vascular function and the endocannabinoid system in spontaneously hypertensive rats (SHR). Functional studies were performed on small mesenteric G3 arteries (sMA) and aortas isolated from SHR and normotensive Wistar Kyoto rats (WKY) treated with URB597 (1 mg/kg; twice daily for 14 days). In the aortas and sMA of SHR, endocannabinoid levels and cannabinoid CB₁ receptor (CB₁R) expression were elevated. The CB₁R antagonist AM251 diminished the methanandamide-evoked relaxation only in the sMA of SHR and enhanced the vasoconstriction induced by phenylephrine and the thromboxane analog U46619 in sMA in SHR and WKY. In the sMA of SHR, URB597 elevated anandamide levels, improved the endothelium-dependent vasorelaxation to acetylcholine, and in the presence of AM251 reduced the vasoconstriction to phenylephrine and enhanced the vasodilatation to methanandamide, and tended to reduce hypertrophy. In the aortas, URB597 elevated endocannabinoid levels improved the endothelium-dependent vasorelaxation to acetylcholine and decreased CB₁R expression. Our study showed that hypertension and chronic administration of URB597 caused local, resistance artery-specific beneficial alterations in the vascular endocannabinoid system, which may bring further advantages for therapeutic application of pharmacological inhibition of FAAH. Full article

(This article belongs to the Special Issue Molecular Interactions of Arterial Hypertension in Its Target Organs)

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Review

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16 pages, 2078 KiB

Open AccessReview

Molecular Interactions of Arterial Hypertension in Its Target Organs

by Joanna Kućmierz, Weronika Frąk, Ewelina Młynarska, Beata Franczyk and Jacek Rysz

Int. J. Mol. Sci. 2021, 22(18), 9669; https://doi.org/10.3390/ijms22189669 - 07 Sep 2021

Cited by 14 | Viewed by 3947

Abstract

Arterial hypertension (AH) is a major risk factor for the development of cardiovascular diseases. It is estimated that the disease affects between 10% and 20% of the adult population and is responsible for 5.8% of all deaths worldwide. Several pathophysiologic factors are crucial in AH, including inappropriate activation of the renin-angiotensin-aldosterone system, oxidative stress and inflammation. The heart, kidney, brain, retina and arterial blood vessels are prime targets of hypertensive damage. Uncontrolled and untreated AH accelerates the damage to these organs and could cause their failure. Damage to these organs could also manifest as coronary heart disease, cognitive impairment, retinopathy or optic neuropathy. For better understanding, it is important to analyze molecular factors which take part in pathogenesis of AH and hypertension-related target organ damage. In our paper, we would like to focus on molecular interactions of AH in the heart, blood vessels, brain and kidneys. We focus on matrix metalloproteinases, the role of immune system, the renin-angiotensin-aldosterone system and oxidative stress in hypertensive induced organ damage. Full article

(This article belongs to the Special Issue Molecular Interactions of Arterial Hypertension in Its Target Organs)

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