Apolipoprotein A–V modulates multiple atherogenic mechanisms in a mouse model of disturbed clearance of triglyceride-rich lipoproteins

Abstract

ObjectiveApolipoprotein A–V plays an important role in reducing plasma triglyceride levels. We hypothesized that expression of apoA–V would inhibit atherogenesis in apoE−/− mice fed chow diet which is a known model of hypercholesterolemia. Our aim was to study this protective effect and to explore possible mechanisms. Methods and resultsApoA–V+/+ApoE−/− mice expressing human apolipoprotein A–V (hapoA–V) were generated and compared to apoE−/− mice. Atherosclerotic aortic sinus lesion area was 70% smaller in hapoA–V+/+apoE−/−. This was accompanied by a 58% reduction in lesion macrophage content. Furthermore, advanced atherosclerotic lesions in hapoA–V+/+apoE−/− mice showed features of a more stable plaque, manifested by 59% and 37% higher collagen and α-actin content, respectively. Plasma triglyceride and cholesterol levels in hapoA–V+/+apoE−/− mice were 47% and 33% lower, respectively. These were associated with a 33% reduction in very low density lipoprotein triglyceride production and 2-fold acceleration in triglyceride-rich lipoprotein clearance in hapoA–V+/+apoE−/− mice. In addition, hapoA–V+/+apoE−/− mice showed enhanced insulin sensitivity (25% and 15% improvement in glucose tolerance and insulin responsiveness, respectively). Finally, hapoA–V+/+apoE−/− displayed a milder systemic inflammatory response compared to apoE−/− mice, manifested by 22%, 65% and 15% lower plasma levels of TNFα, IL-1β and IL-6, respectively. ConclusionsWe showed that human apolipoprotein A–V is a potent modulator of atherosclerosis in mice through multiple modes of action. These findings may identify apoA–V as a potential therapeutic target for treatment of atherosclerosis.