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<p>Circular RNAs (circRNAs) have emerged as key regulators of cardiovascular pathophysiology. This study intended to mechanistically dissect the role of hsa_circ_0004771 in MI pathogenesis. An in vivo MI mouse model was established, and mouse cardiomyocytes (HL-1 cells) were cultured under hypoxic conditions to construct an in vitro cardiomyocyte injury model. Cardiac function in mice was assessed; serum markers of myocardial injury were quantified. Pathological alterations and levels of apoptosis in myocardial tissues were examined. Key oxidative stress indicators and pro-inflammatory cytokines were detected. Cell viability, cytotoxicity, and apoptosis were evaluated. Endoplasmic reticulum stress (ERS)-related proteins and mitochondrial function were analyzed. Serum samples from acute myocardial infarction (AMI) patients were collected for the detection of hsa_circ_0004771, miR-429, and ATPase sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup> transporting 2(ATP2A2) mRNA expression levels. Furthermore, dual-luciferase reporter assays and RNA pull-down assays were utilized to validate the interactions between miR-429 and circ_0004771 or ATP2A2. Circ_0004771 expression was significantly downregulated in AMI patients and experimental models. Overexpression of circ_0004771 improved cardiac function, ameliorated myocardial injury, decreased infarct size, suppressed oxidative stress markers, and attenuated inflammatory cytokine levels in MI mice. In vitro studies demonstrated that circ_0004771 overexpression alleviated hypoxia-induced injury in HL-1 cardiomyocytes, concurrently mitigating ERS, mitochondrial dysfunction, and calcium overload. Mechanistically, circ_0004771 acted as a sponge of miR-429, thereby upregulating ATP2A2 expression. Inhibition of miR-429 attenuated hypoxia-induced cardiomyocyte damage, while miR-429 overexpression reversed the protective effects of circ_0004771. Silencing of ATP2A2 abrogated the therapeutic benefits of miR-429 inhibition. Circ_0004771 mitigates hypoxia-induced ERS, mitochondrial dysfunction, and calcium overload via the miR-429/ATP2A2 axis in MI.</p>

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hsa_circ_0004771-Targeted Adsorption of miR-429 Mediates ATP2A2 Expression to Attenuate Endoplasmic Reticulum Stress and Mitochondrial Dysfunction During Myocardial Infarction

  • 期刊论文

  • 发表日期：

    2025年7月10日

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  • Ying Deng,
  • Ya Wu,
  • SongChun Liu,
  • YiJun Hou

摘要

Circular RNAs (circRNAs) have emerged as key regulators of cardiovascular pathophysiology. This study intended to mechanistically dissect the role of hsa_circ_0004771 in MI pathogenesis. An in vivo MI mouse model was established, and mouse cardiomyocytes (HL-1 cells) were cultured under hypoxic conditions to construct an in vitro cardiomyocyte injury model. Cardiac function in mice was assessed; serum markers of myocardial injury were quantified. Pathological alterations and levels of apoptosis in myocardial tissues were examined. Key oxidative stress indicators and pro-inflammatory cytokines were detected. Cell viability, cytotoxicity, and apoptosis were evaluated. Endoplasmic reticulum stress (ERS)-related proteins and mitochondrial function were analyzed. Serum samples from acute myocardial infarction (AMI) patients were collected for the detection of hsa_circ_0004771, miR-429, and ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2(ATP2A2) mRNA expression levels. Furthermore, dual-luciferase reporter assays and RNA pull-down assays were utilized to validate the interactions between miR-429 and circ_0004771 or ATP2A2. Circ_0004771 expression was significantly downregulated in AMI patients and experimental models. Overexpression of circ_0004771 improved cardiac function, ameliorated myocardial injury, decreased infarct size, suppressed oxidative stress markers, and attenuated inflammatory cytokine levels in MI mice. In vitro studies demonstrated that circ_0004771 overexpression alleviated hypoxia-induced injury in HL-1 cardiomyocytes, concurrently mitigating ERS, mitochondrial dysfunction, and calcium overload. Mechanistically, circ_0004771 acted as a sponge of miR-429, thereby upregulating ATP2A2 expression. Inhibition of miR-429 attenuated hypoxia-induced cardiomyocyte damage, while miR-429 overexpression reversed the protective effects of circ_0004771. Silencing of ATP2A2 abrogated the therapeutic benefits of miR-429 inhibition. Circ_0004771 mitigates hypoxia-induced ERS, mitochondrial dysfunction, and calcium overload via the miR-429/ATP2A2 axis in MI.