Ferland David J, Darios Emma S, Neubig Richard R, Sjögren Benita, Truong Nguyen, Torres Rosa, Dexheimer Thomas S, Thompson Janice M, Watts Stephanie W
Department of Pharmacology and Toxicology, 1355 Bogue Street Rm B445, Michigan State University, East Lansing, MI 48824-1317, United States.
Department of Pharmacology and Toxicology, 1355 Bogue Street Rm B445, Michigan State University, East Lansing, MI 48824-1317, United States.
Vascul Pharmacol. 2017 Jan;88:30-41. doi: 10.1016/j.vph.2016.11.009. Epub 2016 Nov 24.
Chemerin is an adipokine associated with increased blood pressure, and may link obesity with hypertension. We tested the hypothesis that chemerin-induced contraction of the vasculature occurs via calcium flux in smooth muscle cells. Isometric contraction of rat aortic rings was performed in parallel with calcium kinetics of rat aortic smooth muscle cells to assess the possible signaling pathway. Chemerin-9 (nonapeptide of the chemerin S isoform) caused a concentration-dependent contraction of isolated aorta (EC 100nM) and elicited a concentration-dependent intracellular calcium response (EC 10nM). Pertussis toxin (G inhibitor), verapamil (L-type Ca channel inhibitor), PP1 (Src inhibitor), and Y27632 (Rho kinase inhibitor) reduced both calcium influx and isometric contraction to chemerin-9 but PD098059 (Erk MAPK inhibitor) and U73122 (PLC inhibitor) had little to no effect on either measure of chemerin signaling. Although our primary aim was to examine chemerin signaling, we also highlight differences in the mechanisms of chemerin-9 and recombinant chemerin S. These data support a chemerin-induced contractile mechanism in vascular smooth muscle that functions through G proteins to activate L-type Ca channels, Src, and Rho kinase. There is mounting evidence linking chemerin to hypertension and this mechanism brings us closer to targeting chemerin as a form of therapy.
瑞连蛋白是一种与血压升高相关的脂肪因子，可能将肥胖与高血压联系起来。我们验证了这样一个假说，即瑞连蛋白诱导的血管收缩是通过平滑肌细胞中的钙通量发生的。对大鼠主动脉环进行等长收缩实验，并同时检测大鼠主动脉平滑肌细胞的钙动力学，以评估可能的信号通路。瑞连蛋白-9（瑞连蛋白S异构体的九肽）引起离体主动脉的浓度依赖性收缩（半数有效浓度为100nM），并引发浓度依赖性的细胞内钙反应（半数有效浓度为10nM）。百日咳毒素（G蛋白抑制剂）、维拉帕米（L型钙通道抑制剂）、PP1（Src抑制剂）和Y27632（Rho激酶抑制剂）均可降低瑞连蛋白-9引起的钙内流和等长收缩，但PD098059（细胞外调节蛋白激酶丝裂原活化蛋白激酶抑制剂）和U73122（磷脂酶C抑制剂）对瑞连蛋白信号的这两种测量指标几乎没有影响。尽管我们的主要目的是研究瑞连蛋白信号通路，但我们也强调了瑞连蛋白-9和重组瑞连蛋白S在机制上的差异。这些数据支持了瑞连蛋白在血管平滑肌中诱导收缩的机制，该机制通过G蛋白发挥作用，激活L型钙通道、Src和Rho激酶。越来越多的证据将瑞连蛋白与高血压联系起来，这种机制使我们更接近将瑞连蛋白作为一种治疗靶点。
