Controlled-release mitochondrial protonophore (CRMP) attenuates early- and late-stage atheroprogression in mice

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality, particularly in patients with insulin resistance. Current therapies often target lipid levels but may not fully address the underlying metabolic dysfunction and chronic inflammation that drive atheroprogression. Mitochondrial dysfunction, including altered oxidative phosphorylation and increased reactive oxygen species (ROS) production, plays a critical role in both insulin resistance and inflammatory processes within atherosclerotic plaques. There is an urgent need for novel therapeutic strategies that can safely modulate these fundamental pathways to prevent and treat ASCVD.

Researchers investigated the therapeutic potential of controlled-release mitochondrial protonophore (CRMP), an orally administered formulation of 2,4-dinitrophenol, in a murine model of cardiometabolic syndrome. They used high-fat cholesterol diet (HFCD)-fed low-density lipoprotein receptor-deficient (Ldlr-/-) mice, representing both early and late disease stages of atherogenesis. A control arm received HFCD without CRMP. The study also included chow-fed apolipoprotein E-deficient (Apoe-/-) mice to assess context dependency. Primary endpoints included total plaque burden, lesion size, neutral lipid and lesional macrophage content, plaque stability, plasma and hepatic triglyceride levels, whole-body insulin sensitivity via hyperinsulinemic-euglycemic clamps, and lesional macrophage inflammasome activation and IL-1β release.

CRMP treatment significantly diminished total plaque burden and lesion size compared to HFCD controls in Ldlr-/- mice across both early and late disease stages. Morphometric analysis of the aortic root revealed that CRMP also decreased neutral lipid and lesional macrophage content, while increasing plaque stability. These antiatherogenic effects were associated with lower plasma and hepatic triglyceride levels and improved whole-body insulin sensitivity. Furthermore, CRMP markedly limited lesional macrophage inflammasome activation and IL-1β release, indicating a local immune-dampening effect. Mechanistically, CRMP-mediated reductions in inflammasome activation were driven by mild increases in macrophage mitochondrial inefficiency and lower mitochondrial ROS production. This therapeutic effect was context-dependent, as CRMP failed to curtail lesional IL-1β content and atheroprogression in chow-fed Apoe-/- mice. This highlights the specific metabolic context required for CRMP's efficacy.

CRMP treatment significantly diminished total plaque burden and lesion size in both early and late disease stages in Ldlr-/- mice, alongside reductions in lesional macrophage content and IL-1β release.