Endothelin-1 overexpression exacerbates atherosclerosis and induces aortic aneurysms in apolipoprotein e knockout mice

Abstract

OBJECTIVE - : Endothelin (ET)-1 plays a role in vascular reactive oxygen species production and inflammation. ET-1 has been implicated in human atherosclerosis and abdominal aortic aneurysm (AAA) development. ET-1 overexpression exacerbates high-fat diet-induced atherosclerosis in apolipoprotein E (Apoe) mice. ET-1-induced reactive oxygen species and inflammation may contribute to atherosclerosis progression and AAA development. APPROACH AND RESULTS - : Eight-week-old male wild-type mice, transgenic mice overexpressing ET-1 selectively in endothelium (eET-1), Apoe mice, and eET-1/Apoe mice were fed high-fat diet for 8 weeks. eET-1/Apoe had a 45% reduction in plasma high-density lipoprotein (P<0.05) and presented ≥2-fold more aortic atherosclerotic lesions compared with Apoe (P<0.01). AAAs were detected only in eET-1/Apoe (8/21; P<0.05). Reactive oxygen species production was increased ≥2-fold in perivascular fat, media, or atherosclerotic lesions in the ascending aorta and AAAs of eET-1/Apoe compared with Apoe (P<0.05). Monocyte/macrophage infiltration was enhanced ≥2.5-fold in perivascular fat of ascending aorta and AAAs in eET-1/Apoe compared with Apoe (P<0.05). CD4 T cells were detected almost exclusively in perivascular fat (3/6) and atherosclerotic lesions (5/6) in ascending aorta of eET-1/Apoe (P<0.05). The percentage of spleen proinflammatory Ly-6C monocytes was enhanced 26% by ET-1 overexpression in Apoe (P<0.05), and matrix metalloproteinase-2 was increased 2-fold in plaques of eET-1/Apoe (P<0.05) compared with Apoe. CONCLUSIONS - : ET-1 plays a role in progression of atherosclerosis and AAA formation by decreasing high-density lipoprotein, and increasing oxidative stress, inflammatory cell infiltration, and matrix metalloproteinase-2 in perivascular fat, vascular wall, and atherosclerotic lesions. © 2013 American Heart Association, Inc.