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Role of Orai1 and L-type CaV1.2 channels in Endothelin-1 mediated coronary contraction under ischemia and reperfusion.
Cell Calcium ( IF 4.3 ) Pub Date : 2020-01-03 , DOI: 10.1016/j.ceca.2019.102157 Eva M Calderón-Sánchez 1 , Javier Ávila-Medina 2 , Paula Callejo-García 3 , María Fernández-Velasco 4 , Antonio Ordóñez 1 , Tarik Smani 5
Cell Calcium ( IF 4.3 ) Pub Date : 2020-01-03 , DOI: 10.1016/j.ceca.2019.102157 Eva M Calderón-Sánchez 1 , Javier Ávila-Medina 2 , Paula Callejo-García 3 , María Fernández-Velasco 4 , Antonio Ordóñez 1 , Tarik Smani 5
Affiliation
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Ischemia and Reperfusion (I/R) injuries are associated with coronary artery hypercontracture. They are mainly originated by an exacerbated response to agonists released by endothelium such as Endothelin (ET-1), involving the alteration in intracellular calcium handling. Recent evidences have highlighted the implication of Store-Operated Calcium Channels (SOCC) in intracellular calcium homeostasis in coronary artery. However, little is known about the role of SOCC in the regulation of coronary vascular tone under I/R. The aim of this study was to evaluate the role of SOCC and l-type Ca2+ channels (LTCC) in coronary artery vasoconstriction originated by ET-1 in I/R. We used Left Anterior Descendent coronary artery (LAD) rings, isolated from Wistar rats, to study the contractility and intracellular Ca2+ concentration ([Ca2+]i) under a simulated I/R protocol. We observed that responses to high-KCL induced depolarization and caffeine-induced Ca2+ release are attenuated in coronary artery under I/R. Furthermore, ET-1 addition in ischemia promotes transient and small rise of [Ca2+]i and coronary vascular tone. Meanwhile, these effects are significantly potentiated during reperfusion. The resulting ET-1-induced vasoconstrictions and [Ca2+]i increase were abolished by; GSK-7975A and gadolinium, inhibitors of SOCC; and nifedipine a widely used inhibitor of LTCC. Interestingly, using in situ Proximity Ligation Assay (PLA) in isolated coronary smooth muscle cells we found significant colocalization of LTCC CaV1.2 isoform with Orai1, the pore forming subunit of SOCC, and TRPC1 under I/R. Our data suggest that hypercontraction of coronary artery induced by ET-1 after I/R involves the co-activation of LTCC and SOCC, which colocalize significantly in the sarcolemma of coronary smooth muscle cells.
中文翻译：
Orai1和L型CaV1.2通道在内皮素1介导的缺血和再灌注下冠状动脉收缩中的作用。
缺血和再灌注（I / R）损伤与冠状动脉过度收缩有关。它们主要是由对内皮释放的激动剂如内皮素（ET-1）的加剧反应引起的，涉及细胞内钙处理的改变。最近的证据强调了冠脉内细胞内钙稳态中的储钙通道（SOCC）的含义。然而，关于SOCC在I / R下调节冠状血管张力的作用知之甚少。这项研究的目的是评估SOCC和l型Ca2 +通道（LTCC）在ET-1在I / R中引起的冠状动脉血管收缩中的作用。我们使用了从Wistar大鼠中分离出的左后冠状动脉（LAD）环，在模拟I / R协议下研究收缩力和细胞内Ca2 +浓度（[Ca2 +] i）。我们观察到在I / R下冠状动脉中对高KCL诱导的去极化和咖啡因诱导的Ca 2+释放的反应减弱。此外，在局部缺血中添加ET-1会促进[Ca2 +] i的短暂升高和少量升高以及冠状动脉血管紧张度。同时，在再灌注期间这些效应被显着增强。消除了由ET-1引起的血管收缩和[Ca2 +] i的增加；GSK-7975A和g，SOCC抑制剂；硝苯地平是一种广泛使用的LTCC抑制剂。有趣的是，在离体冠状动脉平滑肌细胞中使用原位邻近连接测定法（PLA），我们发现LTCC CaV1.2亚型与Orai1，SOCC的成孔亚基和TRPC1在I / R下显着共定位。
更新日期：2020-01-04
中文翻译：
Orai1和L型CaV1.2通道在内皮素1介导的缺血和再灌注下冠状动脉收缩中的作用。
缺血和再灌注（I / R）损伤与冠状动脉过度收缩有关。它们主要是由对内皮释放的激动剂如内皮素（ET-1）的加剧反应引起的，涉及细胞内钙处理的改变。最近的证据强调了冠脉内细胞内钙稳态中的储钙通道（SOCC）的含义。然而，关于SOCC在I / R下调节冠状血管张力的作用知之甚少。这项研究的目的是评估SOCC和l型Ca2 +通道（LTCC）在ET-1在I / R中引起的冠状动脉血管收缩中的作用。我们使用了从Wistar大鼠中分离出的左后冠状动脉（LAD）环，在模拟I / R协议下研究收缩力和细胞内Ca2 +浓度（[Ca2 +] i）。我们观察到在I / R下冠状动脉中对高KCL诱导的去极化和咖啡因诱导的Ca 2+释放的反应减弱。此外，在局部缺血中添加ET-1会促进[Ca2 +] i的短暂升高和少量升高以及冠状动脉血管紧张度。同时，在再灌注期间这些效应被显着增强。消除了由ET-1引起的血管收缩和[Ca2 +] i的增加；GSK-7975A和g，SOCC抑制剂；硝苯地平是一种广泛使用的LTCC抑制剂。有趣的是，在离体冠状动脉平滑肌细胞中使用原位邻近连接测定法（PLA），我们发现LTCC CaV1.2亚型与Orai1，SOCC的成孔亚基和TRPC1在I / R下显着共定位。
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