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

Abstract

OBJECTIVE:

Apolipoprotein 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 RESULTS:

ApoA-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.

CONCLUSIONS:

We 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.

• Authors: Itamar Grosskopf, Aviv Shaish, Arnon Afek, Shay Shemesh, Dror Harats, Yehuda Kamari
• Journal: Atherosclerosis (Atherosclerosis) Vol. 224 Issue 1 Pg. 75-83 (Sep 2012) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 22809445 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• APOA5 protein, human
• Actins
• Apolipoprotein A-V
• Apolipoproteins A
• Apolipoproteins E
• Lipoproteins
• Lipoproteins, VLDL
• Triglycerides
• very low density lipoprotein triglyceride
• Cholesterol

Topics

• Actins
• Animals
• Apolipoprotein A-V
• Apolipoproteins A (metabolism)
• Apolipoproteins E (deficiency)
• Atherosclerosis (metabolism, pathology)
• Cholesterol (blood)
• Humans
• Lipoproteins (metabolism)
• Lipoproteins, VLDL (blood)
• Male
• Mice
• Triglycerides (blood)