Stimulatory Effects of Cardiotrophin 1 on Atherosclerosis
Cardiotrophin 1 (CT-1), an interleukin-6 family cytokine, was recently shown to be expressed in the intima of early atherosclerotic lesions in the human carotid artery. CT-1 stimulates proatherogenic molecule expression in human vascular endothelial cells and monocyte migration. However, it has not been reported whether CT-1 accelerates atherosclerosis. This study was performed to examine the stimulatory effects of CT-1 on human macrophage foam cell formation and vascular smooth muscle cell migration and proliferation in vitro, and on the development of atherosclerotic lesions in apolipoprotein E–deficient (ApoE−/−) mice in vivo. CT-1 was expressed at high levels in endothelial cells and macrophages in both humans and ApoE−/− mice. CT-1 significantly enhanced oxidized low-density lipoprotein–induced foam cell formation associated with increased levels of CD36 and acyl-CoA:cholesterol acyltransferase-1 expression in human monocyte–derived macrophages. CT-1 significantly stimulated the migration, proliferation, and collagen-1 expression in human aortic vascular smooth muscle cells. Four-week infusion of CT-1 into ApoE−/− mice significantly accelerated the development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration, vascular smooth muscle cell proliferation, and collagen-1 content in the aortic wall. Activation of inflammasome, such as apoptosis-associated speck-like protein containing a caspase recruitment domain, nuclear factor κB, and cyclooxygenase-2, was observed in exudate peritoneal macrophages from ApoE−/− mice infused with CT-1. Infusion of anti–CT-1–neutralizing antibody alone into ApoE−/− mice significantly suppressed monocyte/macrophage infiltration in atherosclerotic lesions. These results indicate that CT-1 accelerates the development of atherosclerotic lesions by stimulating the inflammasome, foam cell formation associated with CD36 and acyl-CoA:cholesterol acyltransferase-1 upregulation in macrophages, and migration, proliferation, and collagen-1 production in vascular smooth muscle cells.
- Received May 5, 2013.
- Revision received May 24, 2013.
- Accepted August 16, 2013.
- © 2013 American Heart Association, Inc.