Regulation of endothelial nitric oxide synthase in cardiac remodeling

Musicante, Meryl; Kim, Hannah; Chen, Yuanjian; Liao, Fang Hsuean; Bhattacharya, Syamal K.; Lu, Lu; Sun, Yao

doi:10.1016/j.ijcard.2022.05.013

Cited by 8 publications

(6 citation statements)

References 41 publications

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“…Cardiac in ammation is important in the pathogenesis of Cr (VI) exposure [23]. eNOS plays a major role in the toxicity of heart tissue [24]. The results demonstrated that apelin-13 treatment counteracted the K 2 Cr 2 O 7 -induced decrease in eNOS expression.…”

Section: Discussionmentioning

confidence: 92%

Apelin-13 Alleviates Hexavalent Chromium-Induced Myocardial Injury by Inhibiting ROS-mediated Oxidative Damage and Regulating Multiple Signals

Zhang

Liu³

et al. 2022

Preprint

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Hexavalent chromium (Cr (VI)) from environmental pollution shows severe toxicity towards human organs by causing oxidative damage. Apelin-13 may inhibit oxidative damage by blocking ROS accumulation and regulating multiple signals. However, whether apelin-13 can attenuate Cr (VI)-induced toxicity has not been explored. Herein, the protective effect and molecular mechanism of apelin-13 against K2Cr2O7-induced cardiotoxicity in vitro and in vivo were evaluated. Results show that apelin-13 significantly inhibited K2Cr2O7-induced H9c2 cytotoxicity and apoptosis, followed by the attenuated PARP cleavage and caspase activation. Further investigation revealed that apelin-13 co-treatment effectively suppressed K2Cr2O7-induced oxidative damage by inhibiting ROS accumulation. Moreover, apelin-13 co-treatment dramatically normalized MAPKs and PI3K/AKT pathways in K2Cr2O7-treated H9c2 cells. Importantly, apelin-13 administration in vivo effectively attenuated myocardial fibrosis, improved angiogenesis, and inhibited myocardial abnormal proliferation and apoptosis. Ultimately, it alleviated K2Cr2O7-induced myocardial injury in rats. Taken together, our findings validated the strategy of the use of apelin-13 to effectively combat Cr (VI)-induced myocardial injury.

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Section: Discussionmentioning

confidence: 92%

Apelin-13 Alleviates Hexavalent Chromium-Induced Myocardial Injury by Inhibiting ROS-mediated Oxidative Damage and Regulating Multiple Signals

Zhang

Liu³

et al. 2022

Preprint

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“…Reduced levels of PKG and cGMP in HFpEF cardiac homogenates suggests disruption of the NO axis in HFpEF ( Van Heerebeek et al, 2006 ). Recent genetic studies have also identified variants in eNOS as modifiers for HCM severity ( Musicante et al, 2022 ).…”

Section: Mechanisms Of Cardiac Pathophysiology In the Context Of Endo...mentioning

confidence: 99%

Endothelial cell dysfunction in cardiac disease: driver or consequence?

Allbritton-King,

García-Cardeña

2023

Front. Cell Dev. Biol.

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The vascular endothelium is a multifunctional cellular system which directly influences blood components and cells within the vessel wall in a given tissue. Importantly, this cellular interface undergoes critical phenotypic changes in response to various biochemical and hemodynamic stimuli, driving several developmental and pathophysiological processes. Multiple studies have indicated a central role of the endothelium in the initiation, progression, and clinical outcomes of cardiac disease. In this review we synthesize the current understanding of endothelial function and dysfunction as mediators of the cardiomyocyte phenotype in the setting of distinct cardiac pathologies; outline existing in vivo and in vitro models where key features of endothelial cell dysfunction can be recapitulated; and discuss future directions for development of endothelium-targeted therapeutics for cardiac diseases with limited existing treatment options.

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“…However, the involvement of multiple biochemical signal transduction modules, such as Ca 2+ , phosphoinositide 3-kinase/kinase B (PI3K/AKT), Ras/Raf/extracellular signal-regulated kinase 1/2 (ERK1/2), titin-associated proteins, calcineurin/nuclear factor of activated T-cells (CaN/NFAT), mammalian target of rapamycin (mTOR), growth factors, and Gq protein-coupled receptors in regulating the cardiomyocyte hypertrophic response to the altered force generation has been demonstrated by multiple studies [15,17,18]. In addition to the signaling modules, a few studies have underscored the remodeling of the cardiomyocyte metabolic network at the early stages of disease progression and its influence on cardiomyocyte hypertrophic growth and remodeling [14,[20][21][22][23]. According to these studies, in HCM, cardiomyocytes revert to a fetal metabolic profile, characterized by elevated glucose dependency and diminished oxidative capacity [14].…”

Section: Introductionmentioning

confidence: 99%

“…According to these studies, in HCM, cardiomyocytes revert to a fetal metabolic profile, characterized by elevated glucose dependency and diminished oxidative capacity [14]. Deficiencies in ATP production, unbalanced reactive oxygen species (ROS) homeostasis, and dysfunctional nitric oxide synthases (NOS) activity are also re-2 ported in hypertrophic cardiomyopathy affecting cardiomyocyte growth and remodeling [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Modeling Cardiomyocyte Signaling and Metabolism Predicts Genotype to Phenotype Mechanisms in Hypertrophic Cardiomyopathy

Khalilimeybodi,

Saucerman,

Rangamani

2023

Preprint

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Familial hypertrophic cardiomyopathy (HCM) is a significant precursor of heart failure and sudden cardiac death, primarily caused by mutations in sarcomeric and structural proteins. Despite the extensive research on the HCM genotype, the complex, context-specific nature of many signaling and metabolic pathways linking the HCM genotype to phenotype has hindered therapeutic advancements for patients. To address these challenges, here, we have developed a computational systems biology model of HCM at the cardiomyocyte level. Utilizing a stochastic logic-based ODE method, we integrate subcellular systems in cardiomyocytes that jointly modulate HCM genotype to phenotype, including cardiac signaling, metabolic, and gene regulatory networks, as well as posttranslational modifications linking these networks. After validating with experimental data on changes in activity of signaling species in HCM context and transcriptomes of two HCM mouse models (R403Q-αMyHC and R92W-TnT), the model predicts significant changes in cardiomyocyte metabolic functions such as ATP synthase deficiency and a transition from fatty acids to carbohydrate metabolism in HCM. The model indicated major shifts in glutamine-related metabolism and increased apoptosis after HCM-induced ATP synthase deficiency. Aligned with prior experimental studies, we predicted that the transcription factors STAT, SRF, GATA4, TP53, and FoxO are the key regulators of cardiomyocyte hypertrophy and apoptosis in HCM. Using the model, we identified shared (e.g., activation of PGC1αby AMPK, and FHL1 by titin) and context-specific mechanisms (e.g., regulation of Ca2+sensitivity by titin in HCM patients) that could control genotype to phenotype transition in HCM across different species or mutations. We also predicted potential combination drug targets for HCM (e.g., mavacamten paired with ROS inhibitors) preventing or reversing HCM phenotype (i.e., hypertrophic growth, apoptosis, and metabolic remodeling) in cardiomyocytes. This study provides new insights into mechanisms linking genotype to phenotype in familial hypertrophic cardiomyopathy and offers a framework for assessing new treatments and exploring variations in HCM experimental models.

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Regulation of endothelial nitric oxide synthase in cardiac remodeling

Cited by 8 publications

References 41 publications

Apelin-13 Alleviates Hexavalent Chromium-Induced Myocardial Injury by Inhibiting ROS-mediated Oxidative Damage and Regulating Multiple Signals

Apelin-13 Alleviates Hexavalent Chromium-Induced Myocardial Injury by Inhibiting ROS-mediated Oxidative Damage and Regulating Multiple Signals

Endothelial cell dysfunction in cardiac disease: driver or consequence?

Modeling Cardiomyocyte Signaling and Metabolism Predicts Genotype to Phenotype Mechanisms in Hypertrophic Cardiomyopathy

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