Acta Pharmacol Sin. 2026 Jul 27. doi: 10.1038/s41401-026-01887-6. Online ahead of print.
ABSTRACT
Aortic dissection (AD) is a catastrophic cardiovascular syndrome with an in-hospital mortality of more than 90%. We previously identified oxidative inactivation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) at cysteine 674 (C674) as a driver of aortic smooth muscle cell (ASMC) phenotypic switching. However, its causal impact on autophagic flux and AD remains unresolved. SERCA2 C674S mutant knock-in (SKI) mice, human AD specimens, and primary ASMCs were subjected to quantitative proteomics, histopathology, and autophagy flux assays. Interventions included Ca2+ chelation (BAPTA-AM), endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyrate, mammalian target of rapamycin (mTOR) inhibitor rapamycin, redox modulator Tempol, calcineurin inhibitor cyclosporine A, peroxisome-proliferator-activated receptor γ (PPARγ) agonist pioglitazone, and SERCA2 agonist [6]-gingerol. Therapeutic efficacy was evaluated in β-aminopropionitrile (BAPN)-induced AD. Human AD specimens and SKI aortas displayed suppressed autophagy within the tunica media. SERCA2 dysfunction activated PI3K-AKT-mTOR signaling pathway, reduced TFEB and Rab7, and impaired autophagosome-lysosome fusion in ASMCs. These defects were rescued by BAPTA-AM, 4-phenylbutyrate, rapamycin, Tempol, or [6]-gingerol, but not by calcineurin or pioglitazone. In vivo, rapamycin and [6]-gingerol restored medial autophagy, suppressed ASMC synthetic phenotype, lowered AD incidence and severity, and preserved medial integrity in BAPN-treated SKI mice. In conclusion, oxidative SERCA2 inactivation evokes cytosolic Ca2+ overload, couples ER/oxidative stress to mTOR hyper-activation, and blunts autophagic flux, thereby establishing a self-amplifying loop that precipitates AD. We define a previously unrecognized SERCA2-Ca2+-mTOR-autophagy axis as a guardian of aortic wall homeostasis and establish autophagy rebalancing and SERCA2 activation as mechanistically grounded therapeutic strategies against AD.
PMID:42509384 | DOI:10.1038/s41401-026-01887-6