Enhanced Mitochondrial Transient Receptor Potential Channel, Canonical Type 3-Mediated Calcium Handling in the Vasculature From Hypertensive Rats.
Enhanced Mitochondrial Transient Receptor Potential Channel, Canonical Type 3-Mediated Calcium Handling in the Vasculature From Hypertensive Rats.
复制标题
增强线粒体瞬时受体电位通道，高血压大鼠脉管系统中典型 3 型介导的钙处理。
DOI：
10.1161/jaha.117.005812
复制
发表时间：
2017-07-15
影响因子：
5.4
通讯作者：
Zhu Z
中科院分区：
文献类型：
--
作者：
Wang B;Xiong S;Lin S;Xia W;Li Q;Zhao Z;Wei X;Lu Z;Wei X;Gao P;Liu D;Zhu Z
线粒体Ca 2+稳态是调节线粒体活性氧（ROS）产生和三磷酸腺苷产生的基础。最近，瞬时受体电位通道，典型的3型（TRPC 3），已被证明定位于线粒体，并发挥作用，在维持线粒体钙稳态。抑制TRPC 3减弱自发性高血压大鼠（SHR）血管钙内流。然而，线粒体TRPC 3是否通过增加线粒体钙处理和ROS产生参与高血压仍然是难以捉摸的。在这项研究中，我们证明了与Wistar京都大鼠相比，SHR血管系统中纯化线粒体中TRPC 3表达增加，这有助于增强线粒体钙摄取和ROS生成。此外，TRPC 3的特异性抑制剂Pyr3抑制TRPC 3，显著降低血管线粒体ROS的产生和H2O2的合成，并增加腺苷三磷酸含量。给予替米沙坦可改善这些异常。这一有益作用与通过恢复SHR血管中丙酮酸脱氢酶的活性来改善线粒体呼吸功能有关。在体内，长期给予替米沙坦可抑制TRPC 3介导的过量线粒体ROS生成和SHR血管系统中的血管收缩。更重要的是，TRPC 3基因敲除小鼠通过减少血管紧张素II诱导的线粒体ROS生成，表现出显着改善高血压。总之，我们提供了实验证据的一个潜在的机制，增强TRPC 3活性在细胞质和线粒体水平有助于氧化还原信号和钙失调的血管系统从SHR。血管紧张素II或替米沙坦可通过靶向TRPC 3调节[Ca2+]mito、ROS产生和线粒体能量代谢。
Mitochondrial Ca2+ homeostasis is fundamental to the regulation of mitochondrial reactive oxygen species (ROS) generation and adenosine triphosphate production. Recently, transient receptor potential channel, canonical type 3 (TRPC3), has been shown to localize to the mitochondria and to play a role in maintaining mitochondrial calcium homeostasis. Inhibition of TRPC3 attenuates vascular calcium influx in spontaneously hypertensive rats (SHRs). However, it remains elusive whether mitochondrial TRPC3 participates in hypertension by increasing mitochondrial calcium handling and ROS production. In this study we demonstrated increased TRPC3 expression in purified mitochondria in the vasculature from SHRs, which facilitates enhanced mitochondrial calcium uptake and ROS generation compared with Wistar‐Kyoto rats. Furthermore, inhibition of TRPC3 by its specific inhibitor, Pyr3, significantly decreased the vascular mitochondrial ROS production and H2O2 synthesis and increased adenosine triphosphate content. Administration of telmisartan can improve these abnormalities. This beneficial effect was associated with improvement of the mitochondrial respiratory function through recovering the activity of pyruvate dehydrogenase in the vasculature of SHRs. In vivo, chronic administration of telmisartan suppressed TRPC3‐mediated excessive mitochondrial ROS generation and vasoconstriction in the vasculature of SHRs. More importantly, TRPC3 knockout mice exhibited significantly ameliorated hypertension through reduction of angiotensin II–induced mitochondrial ROS generation. Together, we give experimental evidence for a potential mechanism by which enhanced TRPC3 activity at the cytoplasmic and mitochondrial levels contributes to redox signaling and calcium dysregulation in the vasculature from SHRs. Angiotensin II or telmisartan can regulate [Ca2+]mito, ROS production, and mitochondrial energy metabolism through targeting TRPC3.