The importance of mitochondrial dysfunction and oxidative stress has been indicated in the progression of heart failure (HF). The molecular mechanisms, however, remain to be fully elucidated. This study aimed to explore the role and underlying mechanism of secreted frizzled-related protein 4 (SFRP4) in these two events in HF. Mice with HF were developed using transverse aortic constriction, and hematoxylin-eosin staining, MASSON staining, and Terminal deoxynucleotidyl transferase (TdT)-mediated 2'-Deoxyuridine 5'- Triphosphate nick end labeling (TUNEL assays) were conducted to detect morphological damage in the myocardial tissues of mice. HL-1 mouse cardiomyocytes were induced with isoproterenol (ISO), and cell viability and apoptosis were examined using cell counting kit-8 and TUNEL assays. SFRP4 and Jumonji domain-containing protein 2A (JMJD2A) were highly expressed in myocardial tissues. Suppression of SFRP4 alleviated apoptosis and fibrosis in myocardial tissues of mice. In addition, the extent of mitochondrial dysfunction and oxidative stress in damaged myocardial tissues and HL-1 cells was mitigated by SFRP4 inhibition as well. JMJD2A catalyzed demethylation modification of the SFRP4 promoter, thus promoting SFRP4 transcription in the development of HF. JMJD2A is responsible for SFRP4 transcription activation in the failing hearts of mice. Blockade of JMJD2A or SFRP4 might be a novel therapy effective in mitigating HF progression.

中文翻译：

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JMJD2A 介导 SFRP4 的转录激活并调节心力衰竭中的氧化应激和线粒体功能障碍


线粒体功能障碍和氧化应激在心力衰竭（HF）进展中的重要性已得到证实。然而，其分子机制仍有待充分阐明。本研究旨在探讨分泌型卷曲相关蛋白4（SFRP4）在心力衰竭这两个事件中的作用和潜在机制。使用横主动脉缩窄培养心力衰竭小鼠，并进行苏木精-伊红染色、MASSON 染色和末端脱氧核苷酸转移酶 (TdT) 介导的 2'-脱氧尿苷 5'- 三磷酸缺口末端标记（TUNEL 测定）来检测小鼠的心肌组织。用异丙肾上腺素 (ISO) 诱导 HL-1 小鼠心肌细胞，并使用细胞计数试剂盒 8 和 TUNEL 测定法检查细胞活力和凋亡。 SFRP4 和 Jumonji 结构域蛋白 2A (JMJD2A) 在心肌组织中高表达。抑制 SFRP4 可减轻小鼠心肌组织的细胞凋亡和纤维化。此外，SFRP4 抑制也减轻了受损心肌组织和 HL-1 细胞中线粒体功能障碍和氧化应激的程度。 JMJD2A催化SFRP4启动子的去甲基化修饰，从而促进SFRP4在HF发生过程中的转录。 JMJD2A 负责小鼠衰竭心脏中 SFRP4 转录激活。阻断 JMJD2A 或 SFRP4 可能是一种有效缓解心力衰竭进展的新疗法。