Abstract P3032: Liver-directed Mitochondrial Uncoupling Attenuates The Progression Of Early And Late-stage Atherosclerosis In Mice

• Published in: Circulation research 2022-08, Vol.131 (Suppl_1), p.AP3032-AP3032
• Main Authors: Goedeke, Leigh A, Zhang, Xinbo, Sun, Jonathan, Canfran-Duque, Alberto, Rotllan, Noemi, Nasiri, Ali, Kahn, Mario, Zhang, Xian-Man, Fernandez Hernando, Carlos F, Shulman, Gerald
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.131.suppl_1.P3032

Atherosclerotic cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in people with type 2 diabetes (T2D) and new therapies are urgently needed. We recently developed an orally available, liver-directed controlled-release mitochondrial protonophore (CRMP) and showed that this agent safely reverses hypertriglyceridemia, fatty liver, and T2D in rodent and nonhuman primate models of obesity by promoting a subtle sustained increase in hepatic mitochondrial inefficiency. To determine the effect of CRMP on atherogenesis, we performed intervention studies in which 12-week Western-diet fed Ldlr-/- mice with established atherosclerosis were treated with CRMP (30 mg/kg-day) or vehicle control for an additional 12 weeks. CRMP-treated mice displayed a significant reduction in fasting plasma and hepatic triglyceride content, independently of changes in body weight, fasting plasma glucose, insulin or cholesterol levels. Morphometric analysis of the aortic root and brachiocephalic artery revealed that CRMP treatment significantly reduced total plaque area and neutral lipid accumulation. CRMP treatment also decreased markers of plaque vulnerability, as evidenced by a reduction in necrotic core area and increase in fibrous cap area (P