Song Shanshan, Yamamura Aya, Yamamura Hisao, Ayon Ramon J, Smith Kimberly A, Tang Haiyang, Makino Ayako, Yuan Jason X-J
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Departments of Medicine and Physiology, University of Arizona College of Medicine, Tucson, Arizona;
Kinjo Gakuin University School of Pharmacy, Nagoya, Japan; and.
Am J Physiol Cell Physiol. 2014 Aug 15;307(4):C373-83. doi: 10.1152/ajpcell.00115.2014. Epub 2014 Jun 11.
An increase in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for pulmonary arterial medial hypertrophy in patients with idiopathic pulmonary arterial hypertension (IPAH). Vascular smooth muscle cells (SMC) sense the blood flow shear stress through interstitial fluid driven by pressure or direct exposure to blood flow in case of endothelial injury. Mechanical stimulus can increase [Ca(2+)]cyt. Here we report that flow shear stress raised [Ca(2+)]cyt in PASMC, while the shear stress-mediated rise in [Ca(2+)]cyt and the protein expression level of TRPM7 and TRPV4 channels were significantly greater in IPAH-PASMC than in normal PASMC. Blockade of TRPM7 by 2-APB or TRPV4 by Ruthenium red inhibited shear stress-induced rise in [Ca(2+)]cyt in normal and IPAH-PASMC, while activation of TRPM7 by bradykinin or TRPV4 by 4αPDD induced greater increase in [Ca(2+)]cyt in IPAH-PASMC than in normal PASMC. The bradykinin-mediated activation of TRPM7 also led to a greater increase in [Mg(2+)]cyt in IPAH-PASMC than in normal PASMC. Knockdown of TRPM7 and TRPV4 by siRNA significantly attenuated the shear stress-mediated [Ca(2+)]cyt increases in normal and IPAH-PASMC. In conclusion, upregulated mechanosensitive channels (e.g., TRPM7, TRPV4, TRPC6) contribute to the enhanced [Ca(2+)]cyt increase induced by shear stress in PASMC from IPAH patients. Blockade of the mechanosensitive cation channels may represent a novel therapeutic approach for relieving elevated [Ca(2+)]cyt in PASMC and thereby inhibiting sustained pulmonary vasoconstriction and pulmonary vascular remodeling in patients with IPAH.
肺动脉平滑肌细胞（PASMC）胞质内钙离子浓度（[Ca(2+)]cyt）升高是肺动脉收缩的主要触发因素，也是特发性肺动脉高压（IPAH）患者肺动脉中层肥厚的重要刺激因素。血管平滑肌细胞（SMC）通过压力驱动的组织液感知血流切应力，在内皮损伤时则直接暴露于血流中。机械刺激可增加[Ca(2+)]cyt。在此我们报告，血流切应力可提高PASMC中的[Ca(2+)]cyt，而与正常PASMC相比，IPAH-PASMC中切应力介导的[Ca(2+)]cyt升高以及TRPM7和TRPV4通道的蛋白表达水平显著更高。用2-APB阻断TRPM7或用钌红阻断TRPV4可抑制正常和IPAH-PASMC中切应力诱导的[Ca(2+)]cyt升高，而用缓激肽激活TRPM7或用4αPDD激活TRPV4在IPAH-PASMC中诱导的[Ca(2+)]cyt升高比正常PASMC中更大。缓激肽介导的TRPM7激活在IPAH-PASMC中也导致[Mg(2+)]cyt升高幅度比正常PASMC中更大。用siRNA敲低TRPM7和TRPV4可显著减弱正常和IPAH-PASMC中切应力介导的[Ca(2+)]cyt升高。总之，机械敏感通道（如TRPM7、TRPV4、TRPC6）上调有助于增强IPAH患者PASMC中切应力诱导的[Ca(2+)]cyt升高。阻断机械敏感阳离子通道可能代表一种新的治疗方法，可缓解PASMC中升高的[Ca(2+)]cyt，从而抑制IPAH患者的持续性肺动脉收缩和肺血管重塑。
