Department of Cardiology, People's Hospital, Peking University, No. 11 South Avenue, Xi Zhi Men Xicheng District, Beijing 100044, China.
Biochem Biophys Res Commun. 2011 Apr 22;407(4):807-12. doi: 10.1016/j.bbrc.2011.03.104. Epub 2011 Apr 2.
The Chromogranin A-derived neuropeptide catestatin is an endogenous nicotinic cholinergic antagonist that acts as a pleiotropic hormone. Since catestatin shares several functions with other members derived from the chromogranin/secretogranin protein family and other neuropeptides which exert proliferative effects on vascular smooth muscle cells (VSMCs), we therefore hypothesized that catestatin would regulate VSMC proliferation. The present study demonstrates that catestatin caused a dose-dependent induction of proliferation in rat aortic smooth muscle cells and furthermore evoked a sustained increase in intracellular calcium. This subsequently leaded to enhanced activation of the Ca(2+)/calmodulin-dependent phosphatase, calcineurin and resulted in an activation of the Ca(2+)-dependent transcription factor, nuclear factor of activated T cells (NFAT), initiating transcription of proliferative genes. In addition, cyclosporin A (CsA), a potent inhibitor of calcineurin, abrogated catestatin-mediated effect on VSMCs, indicating that the calcineurin-NFAT signaling is strongly required for catestatin-induced growth of VSMCs. The present study establishes catestatin as a novel proliferative cytokine on vascular smooth muscle cells and this effect is mediated by the Ca(2+)-calcineurin-NFAT signaling pathway.
嗜铬粒蛋白 A 衍生的神经肽 catestatin 是一种内源性烟碱性乙酰胆碱拮抗剂，具有多功能激素的作用。由于 catestatin 与其他来源于嗜铬粒蛋白/分泌颗粒蛋白家族的成员以及其他具有血管平滑肌细胞（VSMC）增殖作用的神经肽具有许多共同的功能，因此我们假设 catestatin 会调节 VSMC 的增殖。本研究表明 catestatin 可引起大鼠主动脉平滑肌细胞的剂量依赖性增殖诱导，并且进一步引起细胞内钙的持续增加。这随后导致钙调蛋白依赖性磷酸酶、钙调神经磷酸酶的活性增强，从而激活 Ca2+依赖性转录因子活化 T 细胞核因子（NFAT），启动增殖基因的转录。此外，钙调神经磷酸酶的强效抑制剂环孢菌素 A（CsA）可阻断 catestatin 对 VSMC 的作用，表明钙调神经磷酸酶-NFAT 信号通路强烈参与 catestatin 诱导的 VSMC 生长。本研究确立了 catestatin 作为血管平滑肌细胞上的一种新型增殖细胞因子，这种作用是通过 Ca2+-钙调神经磷酸酶-NFAT 信号通路介导的。
