ALDH2 rs671 Variant Lowers Blood Pressure Via the Endothelial HSPA5-PIEZO1-eNOS Pathway

The inactivating ALDH2 rs671 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 which ALDH2 rs671 influences blood pressure regulation, remains unclear.

Using Aldh2^E506K (equivalent to the human ALDH2 rs671 polymorphism), Aldh2 global knockout, and endothelial cell-specific Aldh2 knockout 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.

Aldh2^E506K or Aldh2 global 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 by Aldh2^ECKO mice. 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.

Our study provides definitive experimental evidence that ALDH2 rs671 variation or endothelial Aldh2 deficiency 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.