Zhang Lin, Cao Song, Deng Shengli, Yao Gang, Yu Tian
Department of Anesthesiology, Zunyi Medical College, Zunyi, Guizhou, China.
Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical College, Zunyi, Guizhou, China.
PeerJ. 2016 Nov 1;4:e2612. doi: 10.7717/peerj.2612. eCollection 2016.
Ischemic postconditioning (IPC) and ATP sensitive potassium channel (KATP) agonists (e.g. pinacidil and diazoxide) postconditioning are effective methods to defeat myocardial ischemia-reperfusion (I/R) injury, but their specific mechanisms of reducing I/R injury are not fully understood. We observed an intracellular free calcium ([Ca]) overload in Anoxia/reoxygenation (A/R) cardiomyocytes, which can be reversed by KATP agonists diazoxide or pinacidil. The calcium-sensing receptor (CaSR) regulates intracellular calcium homeostasis. CaSR was reported to be involved in the I/R-induced apoptosis in rat cardiomyocytes. We therefore hypothesize that IPC and pinacidil postconditioning (PPC) reduce calcium overload in I/R cardiomyocytes by the down-regulation of CaSR. A/R model was established with adult rat caridomyocyte. mRNA and protein expression of CaSR were detected, IPC, PPC and KATP's effects on [Ca] concentration was assayed too. IPC and PPC ameliorated A/R insult induced [Ca] overload in cardiomyocytes. In addition, they down-regulated the mRNA and protein level of CaSR as we expected. CaSR agonist spermine and KATP blocker glibenclamide offset IPC's effects on CaSR expression and [Ca] modulation. Our data indicate that CaSR down-regulation contributes to the mitigation of calcium overload in A/R cardiomyocytes, which may partially represents IPC and KATP's myocardial protective mechanism under I/R circumstances.
缺血后适应（IPC）和ATP敏感性钾通道（KATP）激动剂（如吡那地尔和二氮嗪）后适应是对抗心肌缺血再灌注（I/R）损伤的有效方法，但其减轻I/R损伤的具体机制尚未完全明确。我们观察到缺氧/复氧（A/R）心肌细胞内存在细胞内游离钙（[Ca]）超载，而KATP激动剂二氮嗪或吡那地尔可使其逆转。钙敏感受体（CaSR）调节细胞内钙稳态。据报道，CaSR参与大鼠心肌细胞I/R诱导的凋亡。因此，我们推测IPC和吡那地尔后适应（PPC）通过下调CaSR来减轻I/R心肌细胞中的钙超载。采用成年大鼠心肌细胞建立A/R模型。检测CaSR的mRNA和蛋白表达，同时测定IPC、PPC和KATP对[Ca]浓度的影响。IPC和PPC改善了A/R损伤诱导的心肌细胞[Ca]超载。此外，正如我们所预期的，它们下调了CaSR的mRNA和蛋白水平。CaSR激动剂精胺和KATP阻滞剂格列本脲抵消了IPC对CaSR表达和[Ca]调节的作用。我们的数据表明，CaSR下调有助于减轻A/R心肌细胞中的钙超载，这可能部分代表了IPC和KATP在I/R情况下的心肌保护机制。
