Lin Lu1, Rui Yan Zhang2, Xiao Qun Wang1, Zhu Hui Liu2, Ying Shen2, Feng Hua Ding2, Hua Meng2, Ling Jie Wang1, Xiao Xiang Yan1, Ke Yang2, Hai Bo Wang2, Li Jin Pu2, Qi Zhang2, Qiu Jing Chen3, Raffaele De Caterina4, Wei Feng Shen5. 1. Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People's Republic of China. 2. Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China. 3. Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People's Republic of China. 4. "Institute of Cardiology and Center of Excellence on Aging, G. d'Annunzio" University - Chieti and Fondazione G. Monasterio, Pisa, Italy rjshenweifeng@126.com rdecater@unich.it. 5. Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People's Republic of China rjshenweifeng@126.com rdecater@unich.it.
Abstract
AIMS: We investigated the association of the adipokine C1q/TNF-related protein (CTRP) 1 with coronary artery disease (CAD), and the biological vascular effects of CTRP1. METHODS AND RESULTS: We analysed CTRP1 levels in sera of CAD patients (n = 451) and non-CAD controls (n = 686), and in coronary endarterectomy specimens (n = 32), non-atherosclerotic internal mammary arteries (n = 26), aortic atherosclerotic plaques (n = 15), and non-atherosclerotic aortic samples (n = 10). C1q/TNF-related protein-levels were higher in sera, endarterectomy specimens, aortic atherosclerotic plaques, and peripheral blood mononuclear cells (PBMCs) from CAD patients compared with controls, and were related to CAD severity. The production of CTRP1 was profusely induced by inflammatory cytokines and itself caused a concentration-dependent expression of adhesion molecules and inflammatory markers in human endothelial cells, human peripheral blood monocytes, and THP-1 cells. C1q/TNF-related protein-1 induced p38-dependent monocyte-endothelium adhesion in vitro and the recruitment of leucocytes to mesenteric venules in C57BL/6 mice. Immunohistochemistry of atherosclerotic femoral arteries exhibited CD68 and VE-cadherin loci-associated increased CTRP1 expression in plaques. Compared with saline, intraperitoneal injection of recombinant CTRP1 protein (200 μg/kg) every other day promoted atherogenesis in apoE(-/-) mice at 24 weeks. However, pro-atherogenic effects were significantly attenuated in CTRP1(-/-)/apoE(-/-) double-knockout mice compared with apoE(-/-) mice, with a consistent decrease in vascular adhesion molecule, phospho-p38 and TNF-α expression and macrophage infiltration in plaque in CTRP1(-/-) and double-knockout mice. Tumour necrosis factor-α-induced expression of adhesion molecules and cytokines were lower in primary endothelial cells and macrophages from CTRP(-/-) mice than in those from C57BL/6 mice. CONCLUSION: C1q/TNF-related protein-1 is a marker of atherosclerosis in humans and promotes atherogenesis in mice. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: We investigated the association of the adipokine C1q/TNF-related protein (CTRP) 1 with coronary artery disease (CAD), and the biological vascular effects of CTRP1. METHODS AND RESULTS: We analysed CTRP1 levels in sera of CAD patients (n = 451) and non-CAD controls (n = 686), and in coronary endarterectomy specimens (n = 32), non-atherosclerotic internal mammary arteries (n = 26), aortic atherosclerotic plaques (n = 15), and non-atherosclerotic aortic samples (n = 10). C1q/TNF-related protein-levels were higher in sera, endarterectomy specimens, aortic atherosclerotic plaques, and peripheral blood mononuclear cells (PBMCs) from CAD patients compared with controls, and were related to CAD severity. The production of CTRP1 was profusely induced by inflammatory cytokines and itself caused a concentration-dependent expression of adhesion molecules and inflammatory markers in human endothelial cells, human peripheral blood monocytes, and THP-1 cells. C1q/TNF-related protein-1 induced p38-dependent monocyte-endothelium adhesion in vitro and the recruitment of leucocytes to mesenteric venules in C57BL/6 mice. Immunohistochemistry of atherosclerotic femoral arteries exhibited CD68 and VE-cadherin loci-associated increased CTRP1 expression in plaques. Compared with saline, intraperitoneal injection of recombinant CTRP1 protein (200 μg/kg) every other day promoted atherogenesis in apoE(-/-) mice at 24 weeks. However, pro-atherogenic effects were significantly attenuated in CTRP1(-/-)/apoE(-/-) double-knockout mice compared with apoE(-/-) mice, with a consistent decrease in vascular adhesion molecule, phospho-p38 and TNF-α expression and macrophage infiltration in plaque in CTRP1(-/-) and double-knockout mice. Tumour necrosis factor-α-induced expression of adhesion molecules and cytokines were lower in primary endothelial cells and macrophages from CTRP(-/-) mice than in those from C57BL/6 mice. CONCLUSION: C1q/TNF-related protein-1 is a marker of atherosclerosis in humans and promotes atherogenesis in mice. Published on behalf of the European Society of Cardiology. All rights reserved.
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