Stimulatory effects of cardiotrophin 1 on atherosclerosis.

Abstract

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.

• Authors: Hanae Konii, Kengo Sato, Sayaka Kikuchi, Hazuki Okiyama, Rena Watanabe, Akinori Hasegawa, Keigo Yamamoto, Fumiko Itoh, Tsutomu Hirano, Takuya Watanabe
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 62 Issue 5 Pg. 942-50 (Nov 2013) ISSN: 1524-4563 [Electronic] United States
• PMID: 24041953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Collagen Type I
• Cytokines
• cardiotrophin 1

Topics

• Animals
• Aorta (drug effects, metabolism, pathology)
• Apolipoproteins E (genetics)
• Atherosclerosis (metabolism, pathology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Collagen Type I (metabolism)
• Cytokines (pharmacology)
• Foam Cells (drug effects, metabolism, pathology)
• Humans
• Mice
• Mice, Knockout
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Signal Transduction (drug effects)