• Yun Zhou, Jin-Yu Wang, Han Feng, Cheng Wang, Li Li, Dan Wu, Hong Lei, Hao Li, and Li-Ling Wu.
• From the Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, People's Republic of China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, People's Republic of China; and Key Laboratory of Cardiovascular Molecular Biology and Regulatory peptides, Ministry of Health, Beijing, People's Republic of China.
• Arterioscler. Thromb. Vasc. Biol. 2014 May 1; 34 (5): 1002-10.

ObjectiveVascular calcification is highly correlated with increased cardiovascular morbidity and mortality. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly identified adipokine that plays important roles in cardiovascular system. Here, we investigated the role of CTRP3 in vascular calcification and its underlying mechanism.Approach And ResultsAdenine-induced chronic renal failure rat model was used to mimic the process of arterial medial calcification. The level of CTRP3 was elevated in serum and abdominal aorta of chronic renal failure rats. Periadventitial gene delivery of CTRP3 significantly accelerated the calcification of abdominal aorta and arterial ring. In cultured vascular smooth muscle cells (VSMCs), CTRP3 increased β-glycerophosphate-induced calcium deposition and alkaline phosphatase activity. Although CTRP3 alone was not sufficient to induce calcification in VSMCs, it upregulated the expression of osteogenic marker genes including runt-related transcription factor 2 (Runx2), bone morphogenetic protein 2, and osteopontin. CTRP3 further enhanced β-glycerophosphate-induced downregulation of smooth muscle α-actin and smooth muscle 22α, while augmenting osteogenic marker expression in VSMCs induced by β-glycerophosphate. In contrast, knockdown of CTRP3 in VSMCs potently suppressed β-glycerophosphate-induced calcification. Mechanistically, knockdown of Runx2 inhibited CTRP3-promoted VSMC calcification. CTRP3 increased extracellular signal-regulated kinase 1/2 phosphorylation and reactive oxygen species production. Preincubation with U0126, an extracellular signal-regulated kinase 1/2 upstream kinase inhibitor, had no effect on CTRP3-induced reactive oxygen species production. However, pretreatment with N-acetyl-l-cysteine, a reactive oxygen species scavenger, suppressed CTRP3-induced extracellular signal-regulated kinase 1/2 phosphorylation. Both N-acetyl-l-cysteine and U0126 significantly inhibited CTRP3-induced upregulation of Runx2 and calcified nodule formation.ConclusionsCTRP3 promotes vascular calcification by enhancing phosphate-induced osteogenic transition of VSMC through reactive oxygen species-extracellular signal-regulated kinase 1/2-Runx2 pathway.

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