Abstract 14578: Dapagliflozin Attenuates Aorta Smooth Muscle Aging and Atherosclerosis via Inhibiting the PPARα Pathway

Objective: SGLT2 inhibitors reduce cardiovascular risks in ASCVD (Atherosclerotic cardiovascular disease) patients independently of glycemic control while the possible mechanisms remain unclear. Smooth muscle senescence is one of the major risk factors exacerbating AS (atherosclerosis). We hypothesized that dapagliflozin inhibits smooth muscle senescence and results in the reducing AS plaque area. Methods & Results: After treatment with dapagliflozin (10umol/L 12h), the cellular senescence and oxidative stress were decreased as measured by expression of P53 (-23%), P21 (-16%) and ROS production (-19%), (all p<0.05) in VSMC induced by the palmitic acid (PA). The trend was also revealed in the AS mouse model. The X-Gal positive VSMC (-20%, p<0.05) as well as the area of SA-β-Gal positive zone (-11%, p<0.05) were significantly reduced after dapagliflozin (0.1mg/kg/day) treatment for 12w. Further analysis of the atherosclerotic lesions revealed a reduction of AS plaque protrusion into the vessel lumen (-21%) and reduced the size of lipid necrotic area (-32%), the thickness of fiber cap (-15%), (all p<0.05), which were indications of instable atherosclerotic plaques. The effects of dapagliflozin on mice aorta were assessed by unbiased transcriptomic analyses. GO and KEGG analysis indicated alterations of the fatty acid metabolic, fatty acid oxidation and PPARα pathway after dapagliflozin treatment. Abnormal activation of PPARα in AS aorta and PA-treated VSMC, were inhibited by dapagliflozin (-18%, -35%, both p<0.05). The protection effects of dapagliflozin on VSMC could be abolished by the PPARα agonist. Conclusions: Dapagliflozin exerts beneficial protecting effects on smooth muscle from senescence and ameliorating lipotoxicity in atherosclerosis by inhibiting the PPARα pathway. These findings suggest a novel mechanistic basis for SGLT2 inhibitor attenuating atherosclerosis mediated by PPARα, linking fatty acid oxidation and cellular senescence.