Abstract 9623: Stimulatory Effects of Cardiotrophin-1 on Atherosclerosis
Cardiotrophin-1 (CT-1), a cytokine belonging to the interleukin-6 superfamily, was recently shown to be expressed in the intima of early atherosclerotic lesions in the human carotid artery. CT-1 stimulates pro-atherogenic molecule expression in human vascular endothelial cells (EC) 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, human EC proliferation, and the migration and proliferation of human vascular smooth muscle cells (VSMCs) 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 ECs 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 (ACAT1) expression in human monocyte-derived macrophages. CT-1 also significantly stimulated the migration and proliferation of human aortic VSMCs, but not EC proliferation. Four-week-infusion of CT-1 into ApoE-/- mice significantly accelerated the development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and VSMC 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 and foam cell formation associated with CD36 and ACAT1 up-regulation in macrophages and VSMC migration and proliferation, contributing to the occurrence of atherosclerotic vascular diseases. Blockade of cardiotrophin-1 is expected to emerge as a new line of therapy against atherosclerosis and its related diseases.
- © 2013 by American Heart Association, Inc.