瞬时受体电位 melastatin-8 激活通过抑制 store-operated calcium entry 诱导正常氧和慢性低氧性肺动脉高压大鼠肺动脉舒张。
Transient Receptor Potential Melastatin-8 Activation Induces Relaxation of Pulmonary Artery by Inhibition of Store-Operated Calcium Entry in Normoxic and Chronic Hypoxic Pulmonary Hypertensive Rats.
机构信息
Key Laboratory of Fujian Province Universities on Ion Channel and Signal Transduction in Cardiovascular Diseases (Y.-P.M., D.-C.L., S.-Y.Z., H.-X.J., J.S.K.S., M.-J.L.) and Department of Physiology and Pathophysiology (Y.-P.M., D.-C.L., S.-Y.Z., H.-X.J., M.-J.L.), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China; and Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland (Y.-P.M., J.S.K.S.).
Key Laboratory of Fujian Province Universities on Ion Channel and Signal Transduction in Cardiovascular Diseases (Y.-P.M., D.-C.L., S.-Y.Z., H.-X.J., J.S.K.S., M.-J.L.) and Department of Physiology and Pathophysiology (Y.-P.M., D.-C.L., S.-Y.Z., H.-X.J., M.-J.L.), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China; and Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland (Y.-P.M., J.S.K.S.)
出版信息
J Pharmacol Exp Ther. 2018 Jun;365(3):544-555. doi: 10.1124/jpet.117.247320. Epub 2018 Apr 5.
Pulmonary hypertension (PH) is characterized by enhanced vasoconstriction and vascular remodeling, which are attributable to the alteration of Ca homeostasis in pulmonary arterial smooth muscle cells (PASMCs). It is well established that store-operated Ca entry (SOCE) is augmented in PASMCs during PH and that it plays a crucial role in PH development. Our previous studies showed that the melastatin-related transient receptor potential 8 (TRPM8) is down-regulated in PASMCs of PH animal models, and activation of TRPM8 causes relaxation of pulmonary arteries (PAs). However, the mechanism of TRPM8-induced PA relaxation is unclear. Here we examined the interaction of TRPM8 and SOCE in PAs and PASMCs of normoxic and chronic hypoxic pulmonary hypertensive (CHPH) rats, a model of human group 3 PH. We found that TRPM8 was down-regulated and TRPM8-mediated cation entry was reduced in CHPH-PASMCs. Activation of TRPM8 with icilin caused concentration-dependent relaxation of cyclopiazonic acid (CPA) and endothelin-1 contracted endothelium-denuded PAs, and the effect was abolished by the SOCE antagonist Gd Application of icilin to PASMCs suppressed CPA-induced Mn quenching and Ca entry, which was reversed by the TRPM8 antagonist -(3-aminopropyl)-2-([(3-methylphenyl)methyl])-oxy--(2-thienylmethyl)benzamide hydrochloride salt (AMTB). Moreover, the inhibitory effects of icilin on SOCE in PA and PASMCs of CHPH rats were significantly augmented due to enhanced SOCE activity in PH. Our results, therefore, demonstrated a novel mechanism of TRPM8-mediated inhibition of SOCE in pulmonary vasculature. Because SOCE is important for vascular remodeling and enhanced vasoconstriction, down-regulation of TRPM8 in PASMCs of CHPH rats may minimize its inhibitory influence to allow unimpeded SOCE activity for PH development.
肺动脉高压（PH）的特征是血管收缩增强和血管重塑，这归因于肺动脉平滑肌细胞（PASMCs）中钙稳态的改变。已经证实，在 PH 期间，储存操纵的钙内流（SOCE）在 PASMCs 中增强，并且它在 PH 发展中起关键作用。我们之前的研究表明，在 PH 动物模型的 PASMCs 中，雷帕霉素相关的瞬时受体电位 8（TRPM8）下调，并且 TRPM8 的激活导致肺血管（PAs）的松弛。然而，TRPM8 诱导的 PA 松弛的机制尚不清楚。在这里，我们检查了在常氧和慢性低氧性肺动脉高压（CHPH）大鼠（一种人类第 3 组 PH 的模型）的 PAs 和 PASMCs 中 TRPM8 和 SOCE 的相互作用。我们发现 TRPM8 下调，并且 CHPH-PASMCs 中的 TRPM8 介导的阳离子内流减少。用 icilin 激活 TRPM8 引起环匹阿尼酸（CPA）的浓度依赖性松弛，内皮素-1 收缩去内皮的 PAs，并且该作用被 SOCE 拮抗剂 Gd 废除。icilin 应用于 PASMCs 抑制 CPA 诱导的 Mn 猝灭和 Ca 内流，并且该作用被 TRPM8 拮抗剂 -（3-氨基丙基）-2-（[（3-甲基苯基）甲基]）-氧基-（2-噻吩基甲基）苯甲酰胺盐酸盐（AMTB）逆转。此外，由于 PH 中 SOCE 活性增强，icilin 对 CHPH 大鼠 PA 和 PASMCs 中 SOCE 的抑制作用明显增强。因此，我们的结果证明了 TRPM8 介导的肺血管 SOCE 抑制的新机制。由于 SOCE 对于血管重塑和增强的血管收缩很重要，因此 CHPH 大鼠 PASMCs 中 TRPM8 的下调可能会使其抑制作用最小化，从而允许无阻的 SOCE 活性以促进 PH 的发展。
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