Abstract FR420: Aldosterone Promotes Aortic Dissection through Lactate/Lactylation-mediated Phenotypic Switching of Vascular Smooth Muscle Cell

Objective: Aortic dissection (AD), a life-threatening vascular condition with limited therapeutic options, is closely associated with vascular smooth muscle cell (VSMC) phenotypic switching. While elevated plasma aldosterone levels have been observed in AD patients, the role of aldosterone in VSMC differentiation and the occurrence of TAD remains elusive. The purpose of this study is to explore the molecular mechanism of aldosterone-induced aortic dissection. Methods and Results: Utilizing an aldosterone-infused C57BL/6 mouse model and human aortic VSMC with multi-omics approaches and a variety of experimental methods, we reveal that aldosterone significantly elevates lactate levels via MR activation. This lactate surge induces extensive protein lactylation modifications, particularly targeting inflammatory regulators and vascular structural proteins. Especially, the lactylation of myosin heavy chain (Myh11) is significantly upregulated in aldosterone group,which affects its binding to actin, influences the vasoconstriction function, and damages the cellular structure. The lactylation-driven molecular changes accelerate VSMC phenotypic switching, disrupt vascular integrity, and ultimately trigger AD development. Importantly, both MR antagonist (spironolactone) and lactate dehydrogenase A inhibitor (GNE-140) effectively mitigated aldosterone-induced pathological changes in vitro. Conclusions: Our findings provide the first proteomic evidence of lactate-mediated lactylation as a key mechanism in aldosterone-induced AD pathogenesis, providing a new insight into the pathological mechanism of AD and identifying MR signaling and lactate metabolism as promising therapeutic targets for AD prevention and treatment.