The YAP/SERCA2a signaling pathway protects cardiomyocytes against reperfusion-induced apoptosis

Abstract

Mitochondria and the endoplasmic reticulum (ER) are known to promote cardiac ischemia/reperfusion (I/R) injury. Overexpression of yes-associated protein (YAP) and/or sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) has been shown to protect cardiomyocytes against I/R-induced injury. Here, we show that activation of the YAP/SERCA2a pathway attenuated mitochondrial damage and ER stress (ERS) to maintain cardiomyocyte viability in the setting of I/R injury. Our results demonstrate that I/R treatment reduced the transcription and expression of <i>YAP</i> and <i>SERCA2a</i>, along with a decline in cardiomyocyte viability. The overexpression of <i>YAP</i> promoted <i>SERCA2a</i> transcription, whereas <i>SERCA2a</i> upregulation did not affect the <i>YAP</i> transcription, suggesting that YAP functions upstream of SERCA2a. Activation of the YAP/SERCA2a pathway suppressed mitochondrial damage by sustaining the mitochondrial redox balance and restoring mitochondrial bioenergetics. Additionally, its activation repressed ERS, reduced calcium overload, and eventually blocked caspase activation. The knockdown of <i>SERCA2a</i> suppressed the protective effects of <i>YAP</i> overexpression on mitochondrial damage and ERS. Overall, our findings reveal that the YAP/SERCA2a pathway attenuates the mitochondrial damage and ERS in response to cardiac I/R injury by regulating the mitochondria-ER communication.