Kojima Akiko, Fukushima Yutaka, Ito Yuki, Ding Wei-Guang, Kitagawa Hirotoshi, Matsuura Hiroshi
Physiology, Shiga University of Medical Science, Otsu, Japan.
J Cardiovasc Pharmacol. 2018 Apr;71(4):248-255. doi: 10.1097/FJC.0000000000000566.
Reperfusion of ischemic myocardium is accompanied by intracellular Ca overload, leading to cardiac dysfunction. However, the mechanisms underlying intracellular Ca overload have yet to be fully elucidated. The mechanism may involve the activation of store-operated Ca entry, which is primarily mediated through the transient receptor potential canonical (TRPC) channels. This study was undertaken to examine the possible involvement of TRPC channels in the development of contractile dysfunction associated with reperfusion of ischemic myocardium using a mouse heart model. The functional expression of TRPC channels was confirmed in mouse ventricular myocytes using immunocytochemistry, Western blotting, and patch-clamp experiments. The left ventricular functions were assessed by measuring left ventricular end-diastolic pressure, left ventricular developed pressure, and its first derivatives in a Langendorff-perfused mouse heart subjected to 30 minutes of normothermic (37°C) global ischemia followed by 60 minutes of reperfusion. Under control conditions, left ventricular functions were deteriorated during reperfusion, which was significantly ameliorated by administration of the TRPC channel blockers 2-aminoethoxydiphenyl borate and La during initial 5 minutes of reperfusion. Our findings suggest that TRPC channels are involved in mediating contractile dysfunction during reperfusion of ischemic myocardium and detect TRPC channels as a potential therapeutic target for preventing myocardial ischemia/reperfusion injury.
缺血心肌的再灌注伴随着细胞内钙超载，导致心脏功能障碍。然而，细胞内钙超载的潜在机制尚未完全阐明。其机制可能涉及储存-操纵性钙内流的激活，这主要通过瞬时受体电位香草酸亚型（TRPC）通道介导。本研究采用小鼠心脏模型，旨在探讨TRPC通道是否参与缺血心肌再灌注相关的收缩功能障碍的发生发展。通过免疫细胞化学、蛋白质印迹和膜片钳实验，证实了TRPC通道在小鼠心室肌细胞中的功能性表达。在Langendorff灌注的小鼠心脏中，通过测量左心室舒张末期压力、左心室发展压及其一阶导数，评估左心室功能。该小鼠心脏先经历30分钟常温（37°C）全心缺血，然后再灌注60分钟。在对照条件下，再灌注期间左心室功能恶化，在再灌注最初5分钟内给予TRPC通道阻滞剂2-氨基乙氧基二苯硼酸和镧可显著改善这种情况。我们的研究结果表明，TRPC通道参与介导缺血心肌再灌注期间的收缩功能障碍，并将TRPC通道作为预防心肌缺血/再灌注损伤的潜在治疗靶点。
