Variant Lowers Blood Pressure Via the Endothelial HSPA5-PIEZO1-eNOS Pathway.

Abstract

BACKGROUND: The inactivatingrs671 polymorphism, present in ≈8% of the global population and up to 30% to 50% of East Asian individuals, has been negatively associated with hypertension. However, the direct role of ALDH2 (aldehyde dehydrogenase 2) dysfunction in this association, as well as the underlying mechanisms by whichrs671 influences blood pressure regulation, remains unclear. METHODS: Using(equivalent to the humanrs671 polymorphism),global knockout, and endothelial cell-specificknockout mice, we assessed changes in blood pressure (BP) using both telemetry and tail-cuff methods. Mass spectrometry, coimmunoprecipitation, and other biological techniques were used to elucidate underlying molecular mechanisms. RESULTS: orglobal knockout mice displayed a significant decrease in BP under both physiological conditions and angiotensin II-induced hypertension, independent of changes in cardiac output and renal function. Mechanistic studies revealed that endothelial ALDH2 dysfunction inhibited the lysosomal degradation of PIEZO1 (piezo-type mechanosensitive ion channel component 1), resulting in its upregulated protein level and activation of the PIEZO1-endothelial nitric oxide synthase BP regulatory axis. PIEZO1 knockdown or channel inhibition by Grammostola spatulata mechanotoxin 4 peptide reversed the reduced BP phenotype exhibited bymice. Using coimmunoprecipitation combined with mass spectrometry, the molecular chaperone HSPA5 (heat shock protein family A member 5) was identified as a novel interactor with PIEZO1, binding to its C-terminus. HSPA5, induced by aldehyde accumulation, functionally enhanced PIEZO1 protein stability upon ALDH2 loss-of-function mutation. Endothelial-specific overexpression of HSPA5 could alleviate angiotensin II-induced hypertension in mice. CONCLUSIONS: Our study provides definitive experimental evidence thatrs671 variation or endothelialdeficiency plays a protective role in BP regulation by activating the HSPA5-PIEZO1-endothelial nitric oxide synthase axis. We also revealed the previously unrecognized role of HSPA5 in maintaining PIEZO1 stability and BP regulation, providing a potential novel intervention target for hypertension therapy.