Song Michael Y, Makino Ayako, Yuan Jason X-J
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093-0725.
Pulm Circ. 2011 Winter;1(1):84-94. doi: 10.4103/2045-8932.78106.
Pulmonary vasoconstriction and vascular remodeling are two major causes for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with idiopathic pulmonary arterial hypertension (IPAH). An increase in cytosolic free Ca(2+) concentration (Ca(2+)) in pulmonary artery smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation, which causes pulmonary vascular remodeling. Store-operated Ca(2+) entry (SOCE), induced by depletion of stored Ca(2+) in the sarcoplasmic reticulum (SR), can increase Ca(2+) in PASMC independent of other means of Ca(2+) entry. Stromal interaction molecule (STIM) proteins, STIM1 and STIM2, were recently identified as both sensors for store depletion and signaling molecules to open store-operated Ca(2+) channels. We previously reported that SOCE was significantly enhanced in PASMC from IPAH patients compared to PASMC from normotensive control subjects. Enhanced SOCE plays an important role in the pathophysiological changes in PASMC associated with pulmonary arterial hypertension. In this study, we examine whether the expression level of STIM1 and STIM2 is altered in IPAH-PASMC compared to control PASMC and whether these putative changes in STIM1/2 expression level are responsible for enhanced SOCE and proliferation in IPAH-PASMC. Compared to control PASMC, the protein expression level of STIM2 was significantly increased whereas STIM1 protein expression was not significantly changed. In IPAH-PASMC, siRNA-mediated knockdown of STIM2 decreased SOCE and proliferation, while knockdown of STIM2 in control PASMC had no effect on either SOCE or proliferation. Overexpression of STIM2 in control PASMC failed to enhance SOCE or proliferation. These data indicate that enhanced protein expression of STIM2 is necessary, but not sufficient, for enhanced SOCE and proliferation of IPAH-PASMC.
肺血管收缩和血管重塑是特发性肺动脉高压（IPAH）患者肺血管阻力升高和肺动脉压力升高的两个主要原因。肺动脉平滑肌细胞（PASMC）中胞质游离Ca(2+)浓度（Ca(2+)）的增加是肺血管收缩的主要触发因素，也是PASMC增殖的重要刺激因素，后者会导致肺血管重塑。由肌浆网（SR）中储存的Ca(2+)耗尽诱导的储存操纵性Ca(2+)内流（SOCE）可独立于其他Ca(2+)内流方式增加PASMC中的Ca(2+)。基质相互作用分子（STIM）蛋白STIM1和STIM2最近被鉴定为储存耗尽的传感器以及打开储存操纵性Ca(2+)通道的信号分子。我们之前报道，与血压正常的对照受试者的PASMC相比，IPAH患者的PASMC中SOCE显著增强。增强的SOCE在与肺动脉高压相关的PASMC病理生理变化中起重要作用。在本研究中，我们研究了与对照PASMC相比，IPAH-PASMC中STIM1和STIM2的表达水平是否改变，以及STIM1/2表达水平的这些假定变化是否导致IPAH-PASMC中SOCE增强和增殖。与对照PASMC相比，STIM2的蛋白表达水平显著增加，而STIM1蛋白表达没有显著变化。在IPAH-PASMC中，siRNA介导的STIM2敲低降低了SOCE和增殖，而对照PASMC中STIM2的敲低对SOCE或增殖均无影响。对照PASMC中STIM2的过表达未能增强SOCE或增殖。这些数据表明，STIM2蛋白表达增强对于IPAH-PASMC中SOCE增强和增殖是必要的，但不是充分的。
