Life sciences · 2025
Regulation of CaV1.2 channel by calpastatin is disturbed in myocardial infarction in rats.
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Hu Huiyuan, Xue Yingchun, Sun Yu, Zhao Yifan, Zhou Shi, Zhao Yan, Liu Shuang, Jiao Guangyu, Hao Liying
Аннотация
AIMS: Calpastatin (CS) is an endogenous inhibitor of calpain, the Ca2+-activated protease. We previously reported that CS can facilitate the opening of the cardiac CaV1.2 channel. However, the pathophysiological implications of the regulatory effects of CS on CaV1.2 channels remain unclear. This study aims to investigate how CS modulates CaV1.2 channels and its role in cardiac ischemic injury.
MATERIALS AND METHODS: CS-specific siRNA or overexpression plasmid was transfected into H9c2 cells, respectively. A rat myocardial infarction (MI) model and two hypoxic models in H9c2 cells were established. The dynamic changes in the expression and localization of CS and CaV1.2 were examined with real-time PCR, western blot and immunofluorescence.
KEY FINDINGS: Knockdown or overexpression of CS led to a corresponding downregulation or upregulation in CaV1.2 expression correspondingly, indicating the direct regulation of CS on CaV1.2. Both CS and CaV1.2 were downregulated in the late stage of infarct myocardium and hypoxic H9c2 cells. Notably, CaV1.2 and CS co-localized at the plasma membrane in normal cardiomyocytes, but this localization was diminished following MI. The concomitant changes in CS and CaV1.2 could not be prevented by MDL28170, a calpain inhibitor, suggesting that mechanisms beyond proteolysis were involved. Moreover, an exogenous peptide derived from CS domain L (CSL) exerts cardioprotective effects by upregulating CaV1.2 channel expression.
SIGNIFICANCE: Our findings, for the first time, reveal that CS directly modulates the expression and function of the CaV1.2 channel, which is impaired under myocardial ischemic condition.
MATERIALS AND METHODS: CS-specific siRNA or overexpression plasmid was transfected into H9c2 cells, respectively. A rat myocardial infarction (MI) model and two hypoxic models in H9c2 cells were established. The dynamic changes in the expression and localization of CS and CaV1.2 were examined with real-time PCR, western blot and immunofluorescence.
KEY FINDINGS: Knockdown or overexpression of CS led to a corresponding downregulation or upregulation in CaV1.2 expression correspondingly, indicating the direct regulation of CS on CaV1.2. Both CS and CaV1.2 were downregulated in the late stage of infarct myocardium and hypoxic H9c2 cells. Notably, CaV1.2 and CS co-localized at the plasma membrane in normal cardiomyocytes, but this localization was diminished following MI. The concomitant changes in CS and CaV1.2 could not be prevented by MDL28170, a calpain inhibitor, suggesting that mechanisms beyond proteolysis were involved. Moreover, an exogenous peptide derived from CS domain L (CSL) exerts cardioprotective effects by upregulating CaV1.2 channel expression.
SIGNIFICANCE: Our findings, for the first time, reveal that CS directly modulates the expression and function of the CaV1.2 channel, which is impaired under myocardial ischemic condition.