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

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.

SUBMITTER: Xu M

PROVIDER: S-EPMC8423579 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Qingda granules (QDG) exhibit antihypertension and multiple-target-organ protection. However, the therapeutic potential of QDG on hypertensive renal injury remains unknown. Therefore, the main objective of the current study is to explore the effects and underlying mechanisms of QDG treatment on renal injury in angiotensin (Ang) II-infused mice. Methods and results: Mice were infused with Ang II (500 ng/kg/min) or saline for 4 weeks with subcutaneously implanted osmotic pumps. After infusion, mice in the Ang II + QDG group were intragastrically administrated with QDG daily (1.145 g/kg/day), whereas the control group and Ang II group were intragastrically administrated with the same amount of double-distilled water. Blood pressure of the mice monitored using the CODA™ noninvasive blood pressure system revealed that QDG treatment significantly attenuated elevated blood pressure. Moreover, hematoxylin-eosin staining indicated that QDG treatment ameliorated Ang II-induced renal morphological changes, including glomerular sclerosis and atrophy, epithelial cell atrophy, and tubular dilatation. RNA-sequencing (RNA-seq) identified 662 differentially expressed transcripts (DETs) in renal tissues of Ang II-infused mice, which were reversed after QDG treatment. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis based on DETs in both comparisons of Ang II vs. Control and Ang II + QDG vs. Ang II identified multiple enriched pathways, including apoptosis and p53 pathways. Consistently, terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining and Annexin V staining revealed that QDG treatment significantly attenuated Ang II-induced cell apoptosis in renal tissues and cultured renal tubular epithelial cell lines (NRK-52E). Furthermore, western blot analysis indicated that Ang II infusion significantly upregulated the protein expression of p53, BCL2-associated X (BAX), cle-caspase-9, and cle-caspase-3, while downregulating the protein expression of BCL-2 in renal tissues, which were attenuated after QDG treatment. Conclusion: Collectively, QDG treatment significantly attenuated hypertensive renal injury, partially by attenuating renal apoptosis and suppressing p53 pathways, which might be the underlying mechanisms.

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

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