Abstract 5160: Apelin Modulates Adipocyte and Inflammatory Cell Processes to Inhibit Atherosclerosis

Abstract

Background: The G-protein coupled receptor APJ and its ligand apelin have many physiological roles in the cardiovascular system, although its overall impact and mechanism of effect on atherosclerosis remain controversial. Methods and Results: Apelin knockout male mice were bred with ApoE knockout (ApoE KO) mice to generate double knockout (DKO) mice. DKO and ApoE KO mice were fed a normal diet for 20 weeks, and atherosclerotic lesions were analyzed histologically in the aortic sinus and by en face analysis. DKO mice developed more atherosclerosis in the thoracoabdominal aorta than ApoE-KO mice (percent plaque area; 5.36±0.55 vs. 2.53±0.54, p<0.05). Lesion area in the aortic sinus was also increased in DKO compared to ApoE-KO (0.30±0.14 vs. 0.15±0.04 mm2, p<0.05). Histological analysis showed that there was no difference in macrophage or smooth muscle content between genotypes, and studies of reactive oxygen species also did not show a significant difference. Because of recent evidence that the apelin-APJ pathway modulates insulin action, we investigated metabolic parameters and those associated with insulin resistance in the mouse models. DKO mice had significantly greater body weight and fat weight, and glucose tolerance testing showed the DKO mice to be insulin resistant. Also, the mRNA expression of TNF-a, IL-6, and MCP-1 in visceral fat tissue was increased in DKO compared with ApoE KO mice. Similarly, in cultured NIH 3T3 cells, apelin treatment decreased LPS-induced MCP-1 mRNA expression. In related studies, we investigated macrophage function in a foam cell assay, and found there was increased CD36 mRNA in aorta, and increased oil red O positive staining cells in peritoneal macrophage preparations from DKO mice compared with those from ApoE-KO mice. Conclusion: Apelin-APJ signaling inhibits atherosclerosis through multiple mechanisms, including modulation of inflammation and metabolic effects in macrophages and adipose tissues.