Abstract 3756: Atherosclerosis Development is Increased in Apelin/Apoe Double Knockout Mice
Background: Signaling of apelin-APJ pathway has been shown to decrease blood pressure, increase vascular NO, antagonize angiotensin II signaling, and increase insulin sensitivity. Despite this vascular protective profile, recent data suggests that apelin may promote atherosclerosis. To further investigate this question, we generated apelin/ApoE double knockout mice and analyzed disease burden.
Methods and Results: We studied ApoE knockout mice (ApoE-KO) and apelin-ApoE double-knockout mice (DKO) on the C57BL/6 homozygous background. After 20 weeks of normal diet or 12 weeks of high fat diet, atherosclerosis lesion area was analyzed. Blood pressure was the same in both genotypes, and there was no significant difference in the plasma levels of total-cholesterol, triglyceride, or HDL-cholesterol. Body weight was similar at 4weeks of age, but DKO mice had increased weight compared to ApoE-KO at sacrifice. En face analysis of atherosclerosis in the aorta showed the DKO had greater lesion development compared to the ApoE-KO (apoE-KO vs. DKO: 2.53±0.54 vs. 5.36±0.55 males normal diet, 2.81±0.52 vs. 8.00±1.48 females normal diet, 3.91±0.42 vs. 6.58±0.56 males high fat diet, 4.32±0.50 vs. 5.90±0.36 females high fat diet. Values are mean % disease, defined as atherosclerotic lesion divided by total aortic area, ± SE.) The lesion area in the aortic sinus was also significantly increased in DKO mice compared to ApoE-KO (apoE-KO vs. DKO: 0.15±0.04 vs. 0.30±0.14 in males and 0.32±0.07 vs. 0.40±0.08 in females. Values are mm2±SD). Immunohistochemisty showed that macrophage infiltration into the atherosclerotic lesion was similar in both genotypes, and there was no difference in the percentage of smooth muscle cell positive area, so cellar components of the lesion was the same in the two groups.
Conclusion: Apelin has an anti-atherogenic effect in the apoE mouse model of athrosclerosis under the conditions employed here. Ongoing experiments are investigating mechanisms that involve vascular wall NO and reactive oxygen species.