SERCA2 gatekeeper role in aortic autophagy: targeting the Ca²⁺-mTOR axis to prevent aortic dissection.

Authors

Lang-Tao Wang, Xun Chen, Jia-Rou Song, Jun-Cai Liu, Sai Wang, Zhen Yang, Rui Su, Jiang-Jie Long, Yu Peng, Ping-Ping Hu, Gang Liu, Si-Qi Li, Hao Chen, Xiao-Yong Tong

Published in

Acta pharmacologica Sinica. Jul 27, 2026. Epub Jul 27, 2026.

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
Bibliographic data and abstract were imported from PubMed on 28 Jul 2026.

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