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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Sialyltransferase7A, a Klf4-responsive gene, promotes cardiomyocyte apoptosis during myocardial infarction
Dongmei Zhang1, Liang Zhu, Chunmei Li
1Department of Physiology, Dalian Medical University, Dalian, People's Republic of China, dongmeizhang72@163.com.
Abstract:
Myocardial infarction (MI) is one major cause of heart failure through its induction of cardiomyocyte death. However, the molecular mechanisms associated with MI-induced cardiomyocyte apoptosis in the context of sialylation of heart are not yet understood. In this study, we found that sialyltransferase7A (Siat7A), one of the members of sialyltransferase family, was significantly increased in the ischemic myocardium, as well as in the human cardiomyocyte cell line AC16 under hypoxic condition. The Sialyl-Tn antigen (Neu5Acα2-6GalNAc-O-Ser/Thr) synthesized by Siat7A also increased in the AC16 cardiomyocytes following hypoxic stimulus. Increased Siat7A promoted cardiomyocyte apoptosis. The knockdown of Siat7A expression reduced cardiomyocyte apoptosis in both of vivo and vitro. Furthermore, the decreased extracellular signal-regulated kinase ERK1 and ERK2 (ERK1/2) activity was involved in the Siat7A-induced cardiomyocyte apoptosis. Notably, we showed that Krüppel-like factor 4 (Klf4), one of the transcription factors, specifically bound to the Siat7A promoter by ChIP assays. Deletion and mutagenesis analysis identified that Klf4 could transactivate the Siat7A promoter region (nt -655 to -636 bp). The upregulated Siat7A expression, which was paralleled by the increased Klf4 in the ischemic myocardium, contributed to cardiomyocyte apoptosis. Our study suggests Siat7A could be a valuable target for developing treatments for MI patients.
Insights
Sialyltransferase7A (Siat7A) promotes heart cell death after myocardial infarction (MI). Targeting Siat7A may offer new treatments for heart failure caused by MI.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Disease
- Cellular Signaling
Background:
- Myocardial infarction (MI) is a primary cause of heart failure, leading to cardiomyocyte death.
- The precise molecular pathways driving MI-induced cardiomyocyte apoptosis, particularly concerning cardiac sialylation, remain unclear.
Purpose of the Study:
- To investigate the role of sialyltransferase7A (Siat7A) in myocardial infarction-induced cardiomyocyte apoptosis.
- To elucidate the molecular mechanisms linking Siat7A to cardiomyocyte death and explore potential therapeutic targets.
Main Methods:
- Quantitative analysis of Siat7A and Sialyl-Tn antigen expression in ischemic myocardium and hypoxic cardiomyocytes.
- In vivo and in vitro experiments involving Siat7A knockdown to assess its impact on cardiomyocyte apoptosis.
- Chromatin immunoprecipitation (ChIP) assays and promoter analysis to identify regulatory factors of Siat7A.
- Assessment of extracellular signal-regulated kinase (ERK1/2) activity.
Main Results:
- Siat7A and its synthesized Sialyl-Tn antigen were upregulated in ischemic myocardium and hypoxic cardiomyocytes.
- Increased Siat7A expression promoted cardiomyocyte apoptosis, while Siat7A knockdown reduced it.
- Siat7A-induced apoptosis involved decreased extracellular signal-regulated kinase (ERK1/2) activity.
- Krüppel-like factor 4 (Klf4) was identified as a direct transcriptional activator of the Siat7A promoter.
Conclusions:
- Sialyltransferase7A (Siat7A) plays a critical role in promoting cardiomyocyte apoptosis following myocardial infarction.
- The Klf4-Siat7A axis contributes to MI-induced cardiac cell death.
- Siat7A represents a potential therapeutic target for mitigating heart failure post-MI.
