International Journal of Molecular Sciences

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18 pages, 4240 KiB

Open AccessArticle

Metabolic Interventions to Prevent Hypertrophy-Induced Alterations in Contractile Properties In Vitro

by Ilvy M. E. Geraets, Will A. Coumans, Agnieszka Strzelecka, Patrick Schönleitner, Gudrun Antoons, Francesco Schianchi, Myrthe M. A. Willemars, Dimitrios Kapsokalyvas, Jan F. C. Glatz, Joost J. F. P. Luiken and Miranda Nabben

Int. J. Mol. Sci. 2021, 22(7), 3620; https://doi.org/10.3390/ijms22073620 - 31 Mar 2021

Cited by 4 | Viewed by 2247

Abstract

(1) Background: The exact mechanism(s) underlying pathological changes in a heart in transition to hypertrophy and failure are not yet fully understood. However, alterations in cardiac energy metabolism seem to be an important contributor. We characterized an in vitro model of adrenergic stimulation-induced [...] Read more.

(1) Background: The exact mechanism(s) underlying pathological changes in a heart in transition to hypertrophy and failure are not yet fully understood. However, alterations in cardiac energy metabolism seem to be an important contributor. We characterized an in vitro model of adrenergic stimulation-induced cardiac hypertrophy for studying metabolic, structural, and functional changes over time. Accordingly, we investigated whether metabolic interventions prevent cardiac structural and functional changes; (2) Methods: Primary rat cardiomyocytes were treated with phenylephrine (PE) for 16 h, 24 h, or 48 h, whereafter hypertrophic marker expression, protein synthesis rate, glucose uptake, and contractile function were assessed; (3) Results: 24 h PE treatment increased expression of hypertrophic markers, phosphorylation of hypertrophy-related signaling kinases, protein synthesis, and glucose uptake. Importantly, the increased glucose uptake preceded structural and functional changes, suggesting a causal role for metabolism in the onset of PE-induced hypertrophy. Indeed, PE treatment in the presence of a PAN-Akt inhibitor or of a GLUT4 inhibitor dipyridamole prevented PE-induced increases in cellular glucose uptake and ameliorated PE-induced contractile alterations; (4) Conclusions: Pharmacological interventions, forcing substrate metabolism away from glucose utilization, improved contractile properties in PE-treated cardiomyocytes, suggesting that targeting glucose uptake, independent from protein synthesis, forms a promising strategy to prevent hypertrophy and hypertrophy-induced cardiac dysfunction. Full article

(This article belongs to the Special Issue Myocardial Infarction and Myocardial Protection)

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16 pages, 3437 KiB

Open AccessArticle

The BDNF rs6265 Polymorphism is a Modifier of Cardiomyocyte Contractility and Dilated Cardiomyopathy

by Frank J. Raucci, Jr., Anand Prakash Singh, Jonathan Soslow, Larry W. Markham, Lin Zhong, Wejdan Aljafar, Natasja Lessiohadi, Cassandra P. Awgulewitsch, Prachi Umbarkar, Qinkun Zhang, Presley L. Cannon, Maciej Buchowski, Joseph T. Roland, Erica J. Carrier, William B. Burnette, Antonis K. Hatzopoulos, Hind Lal and Cristi L. Galindo

Int. J. Mol. Sci. 2020, 21(20), 7466; https://doi.org/10.3390/ijms21207466 - 10 Oct 2020

Cited by 6 | Viewed by 2913

Abstract

Brain-derived neurotrophic factor (BDNF) is a neuronal growth and survival factor that harbors cardioprotective qualities that may attenuate dilated cardiomyopathy. In ~30% of the population, BDNF has a common, nonsynonymous single nucleotide polymorphism rs6265 (Val66Met), which might be correlated with increased risk of [...] Read more.

Brain-derived neurotrophic factor (BDNF) is a neuronal growth and survival factor that harbors cardioprotective qualities that may attenuate dilated cardiomyopathy. In ~30% of the population, BDNF has a common, nonsynonymous single nucleotide polymorphism rs6265 (Val66Met), which might be correlated with increased risk of cardiovascular events. We previously showed that BDNF correlates with better cardiac function in Duchenne muscular dystrophy (DMD) patients. However, the effect of the Val66Met polymorphism on cardiac function has not been determined. The goal of the current study was to determine the effects of rs6265 on BDNF biomarker suitability and DMD cardiac functions more generally. We assessed cardiovascular and skeletal muscle function in human DMD patients segregated by polymorphic allele. We also compared echocardiographic, electrophysiologic, and cardiomyocyte contractility in C57/BL-6 wild-type mice with rs6265 polymorphism and in mdx/mTR (mDMD) mouse model of DMD. In human DMD patients, plasma BDNF levels had a positive correlation with left ventricular function, opposite to that seen in rs6265 carriers. There was also a substantial decrease in skeletal muscle function in carriers compared to the Val homozygotes. Surprisingly, the opposite was true when cardiac function of DMD carriers and non-carriers were compared. On the other hand, Val66Met wild-type mice had only subtle functional differences at baseline but significantly decreased cardiomyocyte contractility. Our results indicate that the Val66Met polymorphism alters myocyte contractility, conferring worse skeletal muscle function but better cardiac function in DMD patients. Moreover, these results suggest a mechanism for the relative preservation of cardiac tissues compared to skeletal muscle in DMD patients and underscores the complexity of BDNF signaling in response to mechanical workload. Full article

(This article belongs to the Special Issue Myocardial Infarction and Myocardial Protection)

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19 pages, 3967 KiB

Open AccessArticle

Role of Muscle-Specific Histone Methyltransferase (Smyd1) in Exercise-Induced Cardioprotection against Pathological Remodeling after Myocardial Infarction

by Qiaoqin Liang, Mengxin Cai, Jiaqi Zhang, Wei Song, Wanyu Zhu, Lei Xi and Zhenjun Tian

Int. J. Mol. Sci. 2020, 21(19), 7010; https://doi.org/10.3390/ijms21197010 - 23 Sep 2020

Cited by 19 | Viewed by 3025

Abstract

Pathological remodeling is the main detrimental complication after myocardial infarction (MI). Overproduction of reactive oxygen species (ROS) in infarcted myocardium may contribute to this process. Adequate exercise training after MI may reduce oxidative stress-induced cardiac tissue damage and remodeling. SET and MYND domain [...] Read more.

Pathological remodeling is the main detrimental complication after myocardial infarction (MI). Overproduction of reactive oxygen species (ROS) in infarcted myocardium may contribute to this process. Adequate exercise training after MI may reduce oxidative stress-induced cardiac tissue damage and remodeling. SET and MYND domain containing 1 (Smyd1) is a muscle-specific histone methyltransferase which is upregulated by resistance training, may strengthen sarcomere assembly and myofiber folding, and may promote skeletal muscles growth and hypertrophy. However, it remains elusive if Smyd1 has similar functions in post-MI cardiac muscle and participates in exercise-induced cardioprotection. Accordingly, we investigated the effects of interval treadmill exercise on cardiac function, ROS generation, Smyd1 expression, and sarcomere assembly of F-actin in normal and infarcted hearts. Adult male rats were randomly divided into five groups (n = 10/group): control (C), exercise alone (EX), sham-operated (S), MI induced by permanent ligation of left anterior descending coronary artery (MI), and MI with interval exercise training (MI + EX). Exercise training significantly improved post-MI cardiac function and sarcomere assembly of F-actin. The cardioprotective effects were associated with increased Smyd1, Trx1, cTnI, and α-actinin expression as well as upregulated ratio of phosphorylated AMP-activated protein kinase (AMPK)/AMPK, whereas Hsp90, MuRF1, brain natriuretic peptide (BNP) expression, ROS generation, and myocardial fibrosis were attenuated. The improved post-MI cardiac function was associated with increased Smyd1 expression. In cultured H9C2 cardiomyoblasts, in vitro treatment with H₂O₂ (50 µmol/L) or AMP-activated protein kinase (AMPK) agonist (AICAR, 1 mmol/L) or their combination for 4 h simulated the effects of exercise on levels of ROS and Smyd1. In conclusion, we demonstrated a novel role of Smyd1 in association with post-MI exercise-induced cardioprotection. The moderate level of ROS-induced upregulation of Smyd1 may be an important target for modulating post-MI cardiac function and remodeling. Full article

(This article belongs to the Special Issue Myocardial Infarction and Myocardial Protection)

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15 pages, 2868 KiB

Open AccessArticle

Corin Overexpression Reduces Myocardial Infarct Size and Modulates Cardiomyocyte Apoptotic Cell Death

by Ryan D. Sullivan, Aiilyan K. Houng, Inna P. Gladysheva, Tai-Hwang M. Fan, Ranjana Tripathi, Guy L. Reed and Dong Wang

Int. J. Mol. Sci. 2020, 21(10), 3456; https://doi.org/10.3390/ijms21103456 - 14 May 2020

Cited by 14 | Viewed by 3364

Abstract

Altered expression of corin, a cardiac transmembrane serine protease, has been linked to dilated and ischemic cardiomyopathy. However, the potential role of corin in myocardial infarction (MI) is lacking. This study examined the outcomes of MI in wild-type vs. cardiac-specific overexpressed corin transgenic [...] Read more.

Altered expression of corin, a cardiac transmembrane serine protease, has been linked to dilated and ischemic cardiomyopathy. However, the potential role of corin in myocardial infarction (MI) is lacking. This study examined the outcomes of MI in wild-type vs. cardiac-specific overexpressed corin transgenic (Corin-Tg) mice during pre-MI, early phase (3, 24, 72 h), and late phase (1, 4 weeks) post-MI. Corin overexpression significantly reduced cardiac cell apoptosis (p < 0.001), infarct size (p < 0.001), and inhibited cleavage of procaspases 3, 9, and 8 (p < 0.05 to p < 0.01), as well as altered the expression of Bcl2 family proteins, Bcl-xl, Bcl2 and Bak (p < 0.05 to p < 0.001) at 24 h post-MI. Overexpressed cardiac corin also significantly modulated heart function (ejection fraction, p < 0.0001), lung congestion (lung weight to body weight ratio, p < 0.0001), and systemic extracellular water (edema, p < 0.05) during late phase post-MI. Overall, cardiac corin overexpression significantly reduced apoptosis, infarct size, and modulated cardiac expression of key members of the apoptotic pathway in early phase post-MI; and led to significant improvement in heart function and reduced congestion in late phase post-MI. These findings suggest that corin may be a useful target to protect the heart from ischemic injury and subsequent post-infarction remodeling. Full article

(This article belongs to the Special Issue Myocardial Infarction and Myocardial Protection)

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13 pages, 1761 KiB

Open AccessArticle

Swiprosin-1/EFhD-2 Expression in Cardiac Remodeling and Post-Infarct Repair: Effect of Ischemic Conditioning

by Zoltán Giricz, András Makkos, Rolf Schreckenberg, Jochen Pöling, Holger Lörchner, Krisztina Kiss, Péter Bencsik, Thomas Braun, Rainer Schulz, Péter Ferdinandy and Klaus-Dieter Schlüter

Int. J. Mol. Sci. 2020, 21(9), 3359; https://doi.org/10.3390/ijms21093359 - 09 May 2020

Cited by 5 | Viewed by 2859

Abstract

Swiprosin-1 (EFhD2) is a molecule that triggers structural adaptation of isolated adult rat cardiomyocytes to cell culture conditions by initiating a process known as cell spreading. This process mimics central aspects of cardiac remodeling, as it occurs subsequent to myocardial infarction. However, expression [...] Read more.

Swiprosin-1 (EFhD2) is a molecule that triggers structural adaptation of isolated adult rat cardiomyocytes to cell culture conditions by initiating a process known as cell spreading. This process mimics central aspects of cardiac remodeling, as it occurs subsequent to myocardial infarction. However, expression of swiprosin-1 in cardiac tissue and its regulation in vivo has not yet been addressed. The expression of swiprosin-1 was analyzed in mice, rat, and pig hearts undergoing myocardial infarction or ischemia/reperfusion with or without cardiac protection by ischemic pre- and postconditioning. In mouse hearts, swiprosin-1 protein expression was increased after 4 and 7 days in myocardial infarct areas specifically in cardiomyocytes as verified by immunoblotting and histology. In rat hearts, swiprosin-1 mRNA expression was induced within 7 days after ischemia/reperfusion but this induction was abrogated by conditioning. As in cultured cardiomyocytes, the expression of swiprosin-1 was associated with a coinduction of arrestin-2, suggesting a common mechanism of regulation. Rno-miR-32-3p and rno-miR-34c-3p were associated with the regulation pattern of both molecules. Moreover, induction of swiprosin-1 and ssc-miR-34c was also confirmed in the infarct zone of pigs. In summary, our data show that up-regulation of swiprosin-1 appears in the postischemic heart during cardiac remodeling and repair in different species. Full article

(This article belongs to the Special Issue Myocardial Infarction and Myocardial Protection)

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17 pages, 7285 KiB

Open AccessArticle

Anti-Myocardial Infarction Effects of Radix Aconiti Lateralis Preparata Extracts and Their Influence on Small Molecules in the Heart Using Matrix-Assisted Laser Desorption/Ionization–Mass Spectrometry Imaging

by Hao Wu, Xi Liu, Ze-yu Gao, Zhen-feng Dai, Ming Lin, Fang Tian, Xin Zhao, Yi Sun and Xiao-ping Pu

Int. J. Mol. Sci. 2019, 20(19), 4837; https://doi.org/10.3390/ijms20194837 - 29 Sep 2019

Cited by 21 | Viewed by 4303

Abstract

Radix Aconiti Lateralis Preparata (fuzi) is the processed product of Aconitum carmichaelii Debeaux tuber, and has great potential anti-myocardial infarction effects, including improving myocardial damage and energy metabolism in rats. However, the effects of Radix Aconiti Lateralis Preparata extracts in a rat model [...] Read more.

Radix Aconiti Lateralis Preparata (fuzi) is the processed product of Aconitum carmichaelii Debeaux tuber, and has great potential anti-myocardial infarction effects, including improving myocardial damage and energy metabolism in rats. However, the effects of Radix Aconiti Lateralis Preparata extracts in a rat model of myocardial infarction have not yet been fully illustrated. Herein, Radix Aconiti Lateral Preparata was used to prepare Radix Aconiti Lateralis Preparata extract (RAE), fuzi polysaccharides (FPS), and fuzi total alkaloid (FTA). Then, we aimed to compare the effects of RAE, FPS, and FTA in MI rats and further explore their influence on small molecules in the heart. We reported that Radix Aconiti Lateralis Preparata extract (RAE) and fuzi total alkaloid (FTA) significantly improved left ventricular function and structure, and reduced myocardial damage and infarct size in rats with myocardial infarction by the left anterior descending artery ligation. In contrast, fuzi polysaccharides (FPS) was less effective than RAE and FTA, indicating that alkaloids might play a major role in the treatment of myocardial infarction. Moreover, via matrix-assisted laser desorption/ionization–mass spectrometry imaging (MALDI–MSI), we further showed that RAE and FTA containing alkaloids as the main common components regulated myocardial energy metabolism-related molecules and phospholipids levels and distribution patterns against myocardial infarction. In particular, it was FTA, not RAE, that could also regulate potassium ions and glutamine to play a cardioprotective role in myocardial infarction, which revealed that an appropriate dose of alkaloids generated more obvious cardiotonic effects. These findings together suggested that Radix Aconiti Lateralis Preparata extracts containing an appropriate dose of alkaloids as its main pharmacological active components exerted protective effects against myocardial infarction by improving myocardial energy metabolism abnormalities and changing phospholipids levels and distribution patterns to stabilize the cardiomyocyte membrane structure. Thus, RAE and FTA extracted from Radix Aconiti Lateralis Preparata are potential candidates for the treatment of myocardial infarction. Full article

(This article belongs to the Special Issue Myocardial Infarction and Myocardial Protection)

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Review

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18 pages, 2664 KiB

Open AccessReview

Linking LOXL2 to Cardiac Interstitial Fibrosis

by Melisse Erasmus, Ebrahim Samodien, Sandrine Lecour, Martin Cour, Oscar Lorenzo, Phiwayinkosi Dludla, Carmen Pheiffer and Rabia Johnson

Int. J. Mol. Sci. 2020, 21(16), 5913; https://doi.org/10.3390/ijms21165913 - 18 Aug 2020

Cited by 19 | Viewed by 4968

Abstract

Cardiovascular diseases (CVDs) are the leading causes of death worldwide. CVD pathophysiology is often characterized by increased stiffening of the heart muscle due to fibrosis, thus resulting in diminished cardiac function. Fibrosis can be caused by increased oxidative stress and inflammation, which is [...] Read more.

Cardiovascular diseases (CVDs) are the leading causes of death worldwide. CVD pathophysiology is often characterized by increased stiffening of the heart muscle due to fibrosis, thus resulting in diminished cardiac function. Fibrosis can be caused by increased oxidative stress and inflammation, which is strongly linked to lifestyle and environmental factors such as diet, smoking, hyperglycemia, and hypertension. These factors can affect gene expression through epigenetic modifications. Lysyl oxidase like 2 (LOXL2) is responsible for collagen and elastin cross-linking in the heart, and its dysregulation has been pathologically associated with increased fibrosis. Additionally, studies have shown that, LOXL2 expression can be regulated by DNA methylation and histone modification. However, there is a paucity of data on LOXL2 regulation and its role in CVD. As such, this review aims to gain insight into the mechanisms by which LOXL2 is regulated in physiological conditions, as well as determine the downstream effectors responsible for CVD development. Full article

(This article belongs to the Special Issue Myocardial Infarction and Myocardial Protection)

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14 pages, 2933 KiB

Open AccessReview

Diagnostic Roles of Postmortem cTn I and cTn T in Cardiac Death with Special Regard to Myocardial Infarction: A Systematic Literature Review and Meta-Analysis

by Zhipeng Cao, Mengyang Zhao, Chengyang Xu, Tianyi Zhang, Yuqing Jia, Tianqi Wang and Baoli Zhu

Int. J. Mol. Sci. 2019, 20(13), 3351; https://doi.org/10.3390/ijms20133351 - 08 Jul 2019

Cited by 28 | Viewed by 7179

Abstract

Background: Cardiac troponin I (cTn I) and cardiac troponin T (cTn T) are currently widely used as diagnostic biomarkers for myocardial injury caused by ischemic heart diseases in clinical and forensic medicine. However, no previous meta-analysis has summarized the diagnostic roles of postmortem [...] Read more.

Background: Cardiac troponin I (cTn I) and cardiac troponin T (cTn T) are currently widely used as diagnostic biomarkers for myocardial injury caused by ischemic heart diseases in clinical and forensic medicine. However, no previous meta-analysis has summarized the diagnostic roles of postmortem cTn I and cTn T. The aim of the present study was to meta-analyze the diagnostic roles of postmortem cTn I and cTn T for cardiac death in forensic medicine, present a systematic review of the previous literature, and determine the postmortem cut-off values of cTn I and cTn T. Methods: We searched multiple databases for the related literature, performed a meta-analysis to investigate the diagnostic roles of postmortem cardiac troponins, and analyzed the receiver operating characteristic (ROC) curve to determine their postmortem cut-off values. Results and Conclusions: The present meta-analysis demonstrated that postmortem cTn I and cTn T levels were increased in pericardial fluid and serum in cardiac death, especially in patients with acute myocardial infarction (AMI). We determined the postmortem cut-off value of cTn I in the pericardial fluid at 86.2 ng/mL, cTn I in serum at 9.5 ng/mL, and cTn T in serum at 8.025 ng/mL. Full article

(This article belongs to the Special Issue Myocardial Infarction and Myocardial Protection)

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