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


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.
The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel-Hashomer, Israel. itamar.grosskopf@sheba.health.gov.il
Itamar
I
Grosskopf
Aviv
A
Shaish
Arnon
A
Afek
Shay
S
Shemesh
Dror
D
Harats
Yehuda
Y
Kamari
D000199:Actins; D000818:Animals; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D051379:Mice; D014280:Triglycerides / Q000097:blood*
C437704:APOA5 protein, human; D000199:Actins; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A; D001057:Apolipoproteins E; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D002784:Cholesterol