Abstract Body (Do not enter title and authors here): Dyslipidemia contributes to oxidative stress, inflammation, and the dedifferentiation, migration, and proliferation of vascular smooth muscle cells (SMCs), ultimately promoting the development and progression of atherosclerosis. Bempedoic acid (BA), an FDA-approved medication for managing dyslipidemia, particularly in patients with statin intolerance, acts by inhibiting adenosine triphosphate-citrate lyase (ACLY), a key enzyme in fatty acid biosynthesis. Recent evidence indicates that BA also exerts lipid-independent, pleiotropic effects by reducing oxidative stress and inflammation. Based on this, we hypothesized that BA could inhibit oxidized low-density lipoprotein (oxLDL)-induced migration, proliferation, and proinflammatory phenotype switching in SMCs by targeting oxidative stress and inflammation.
To test this, human coronary artery SMCs were exposed to varying concentrations of oxLDL, and inflammatory responses were assessed. OxLDL induced a dose- and time-dependent increase in the mRNA and protein expression of a proinflammatory signaling molecule, TRAF3IP2, over a 6-hour period. Pre-treatment with 100 µM BA significantly reduced both TRAF3IP2 mRNA and protein levels. This oxLDL-induced TRAF3IP2 upregulation was found to be reactive oxygen species (ROS)-dependent, driven by NADPH oxidase activity, accompanied by downregulation of antioxidant enzymes superoxide dismutase 1 (SOD1) and catalase (CAT). Notably, BA reversed the suppression of SOD1 and CAT, thereby reducing ROS levels and subsequently decreasing TRAF3IP2 expression.
Moreover, BA inhibited oxLDL-induced phenotypic switching of SMCs toward a proinflammatory state, as evidenced by downregulation of inflammatory markers (LGALS3, OLR1, IL-6, IL-8, ICAM1, VCAM1, and TNF) and restoration of contractile SMC markers (ACTA2 and MYH11). BA also suppressed oxLDL-induced activation of matrix metalloproteinases MMP2 and MMP9, as well as SMC migration and proliferation, without compromising cell viability. Importantly, inhibition of ACLY or AMPK signaling blunted the anti-inflammatory, anti-proliferative, and anti-migratory effects of BA.
Collectively, these findings demonstrate that BA, through ACLY and AMPK pathways, mitigates oxLDL-induced oxidative stress and inflammation, thereby preventing the transition of SMCs to a proinflammatory, pro-migratory, and proliferative phenotype. These results support the potential therapeutic application of BA in vascular atherosclerotic diseases.