Activation of the M3AChR and Notch1/HSF1 Signaling Pathway by Choline Alleviates Angiotensin II-Induced Cardiomyocyte Apoptosis.

Man Xu,Qiong-Ge Li,Qiang Jian,Xiao-Rong Xue,Jian-Yong Sun,Xue-Yuan Bi,Xing-Zhu Lu,Manuela Corte-Real

doi:10.1155/2021/9979706

Abstract

Angiotensin II- (Ang II-) induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Choline exerts cardioprotective effects; however, its effects on Ang II-induced cardiomyocyte apoptosis are unclear. In this study, the role and underlying mechanism of choline in regulating Ang II-induced cardiomyocyte apoptosis were investigated using a model of cardiomyocyte apoptosis, which was induced by exposing neonatal rat cardiomyocytes to Ang II (10−6 M, 48 h). Choline promoted heat shock transcription factor 1 (HSF1) nuclear translocation and the intracellular domain of Notch1 (NICD) expression. Consequently, choline attenuated Ang II-induced increases in mitochondrial reactive oxygen species (mtROS) and promotion of proapoptotic protein release from mitochondria, including cytochrome c, Omi/high-temperature requirement protein A2, and second mitochondrial activator of caspases/direct inhibitor of apoptosis-binding protein with low P. The reversion of these events attenuated Ang II-induced increases in cardiomyocyte size and numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells, presumably via type 3 muscarinic acetylcholine receptor (M3AChR). Indeed, downregulation of M3AChR or Notch1 blocked choline-mediated upregulation of NICD and nuclear HSF1 expression, as well as inhibited mitochondrial apoptosis pathway and cardiomyocyte apoptosis, indicating that M3AChR and Notch1/HSF1 activation confer the protective effects of choline. In vivo studies were performed in parallel, in which rats were infused with Ang II for 4 weeks to induce cardiac apoptosis. The results showed that choline alleviated cardiac remodeling and apoptosis of Ang II-infused rats in a manner related to activation of the Notch1/HSF1 pathway, consistent with the in vitro findings. Taken together, our results reveal that choline impedes oxidative damage and cardiomyocyte apoptosis by activating M3AChR and Notch1/HSF1 antioxidant signaling, and suggest a novel role for the Notch1/HSF1 signaling pathway in the modulation of cardiomyocyte apoptosis.

Highlights

Apoptosis is implicated in various cardiovascular disorders, including myocardial infarction and heart failure (HF) [1], in which the activation of apoptotic pathways may contribute to cardiomyocyte loss and subsequent cardiac dysfunction
Induced heat shock transcription factor 1 (HSF1) nuclear translocation (Figures 7(d)–7(f)). These results indicate that the M3AChR/Notch1 pathway plays a role in the amelioration of Angiotensin II- (Ang II-)induced mitochondrial reactive oxygen species (mtROS) generation and in the choline-mediated upregulation of HSF1 nuclear translocation
angiotensin II (Ang II) activation in the heart has been associated with the development of cardiac hypertrophy and apoptosis, which are thought to be a common pathological basis of myocardial infarction, dilated cardiomyopathy, and early-stage HF

Summary

Introduction

Apoptosis is implicated in various cardiovascular disorders, including myocardial infarction and heart failure (HF) [1], in which the activation of apoptotic pathways may contribute to cardiomyocyte loss and subsequent cardiac dysfunction. The mitochondrial death pathway, called the intrinsic cell death pathway, induces cell death in response to intracellular stressors such as increased oxidative stress, serum deprivation, or deoxyribonucleic acid (DNA) damage [1]. This pathway is regulated by antiapoptotic B-cell lymphoma- (Bcl-) 2 proteins [4]. Previous studies have suggested that the mitochondrial death pathway is involved in cardiovascular diseases that share mitochondrial dysfunction as a common pathogenetic mechanism, including myocardial ischemia/reperfusion (I/R) injury [6] and cardiac remodeling [7]. Regardless, the contribution of the mitochondrial death pathway to Ang II-induced cardiomyocyte apoptosis is unknown

Methods

Results

Conclusion