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

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.

▸ ApoE−/− mouse is a hypercholesterolemic model for human-like atherosclerosis. ▸ Expression of human ApoA-V in ApoE−/− mouse lead to decreased atherosclerosis. ▸ Expression of human ApoA-V enhanced insulin sensitivity and inhibited triglyceride synthesis. ▸ Expression of human ApoA-V accelerated clearance of triglyceride rich lipoproteins. ▸ Expression of human ApoA-V abated inflammation both in the arterial wall and in the circulation.