ATP6AP2 ameliorates inflammation and pyroptosis in heart failure by promoting lysosome-dependent STING degradation.

Inflammatory activation is involved in the pathogenesis of heart failure (HF). ATPase H+-Transporting Accessory Protein 2 (ATP6AP2) is an auxiliary subunit of the V-ATPase, and its role in HF is not fully understood. To assess the role and regulatory mechanisms and therapeutic potential of ATP6AP2 in HF, we used a cardiac-specific ATP6AP2 conditional knockout (CKO) mouse model and observed spontaneous cardiac dysfunction, myocardial fibrosis and cardiomyocyte apoptosis in mice. Further studies showed that ATP6AP2 promoted stimulator of interferon genes (STING) degradation through the lysosome-dependent pathway. ATP6AP2 knockdown significantly upregulated STING protein levels, activated the STING-TBK1-IRF3 signaling axis, and promoted pro-inflammatory factor expression and cardiomyocyte apoptosis. In mice with myocardial infarction (MI), myocardial overexpression of ATP6AP2 or treatment with H-151 inhibited the activation of the STING signaling pathway, ameliorated cardiomyocyte apoptosis and inflammatory responses, thereby improving cardiac function. In addition, in macrophages treated with conditioned medium from hypoxia-exposed cardiomyocytes, the levels of pyroptosis-related proteins were markedly increased, whereas ATP6AP2 overexpression or STING inhibition reduced pyroptosis. ATP6AP2 likewise attenuates inflammation and pyroptosis caused by hypoxia in cardiac organoids. In conclusion, activating ATP6AP2 could serve as a promising therapeutic option in HF.