Activation of Transient Receptor Potential Melastatin Subtype 8 Attenuates Cold-Induced Hypertension Through Ameliorating Vascular Mitochondrial Dysfunction.
Activation of Transient Receptor Potential Melastatin Subtype 8 Attenuates Cold-Induced Hypertension Through Ameliorating Vascular Mitochondrial Dysfunction.
复制标题
瞬时受体电位 Melastatin 亚型 8 的激活通过改善血管线粒体功能障碍减轻寒冷诱发的高血压
DOI：
10.1161/jaha.117.005495
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发表时间：
2017-08-02
影响因子：
5.4
通讯作者：
Zhu Z
中科院分区：
文献类型：
--
作者：
Xiong S;Wang B;Lin S;Zhang H;Li Y;Wei X;Cui Y;Wei X;Lu Z;Gao P;Li L;Zhao Z;Liu D;Zhu Z
环境冷致高血压是常见的，但如何治疗冷致高血压仍然是一个障碍。瞬时受体电位美拉他汀亚型8 （TRPM8）是一种温和的冷感应非选择性阳离子通道，可被薄荷醇激活。关于薄荷醇激活TRPM8对冷诱导高血压患者线粒体Ca2+稳态和血管功能的影响，我们知之甚少。培养野生型或Trpm8−/−小鼠的原代血管平滑肌细胞。在体外，我们证实了肌浆网驻留TRPM8参与了血管平滑肌细胞中细胞和线粒体Ca2+稳态的调节。薄荷醇拮抗血管紧张素II激活TRPM8，通过保持丙酮酸脱氢酶活性，诱导线粒体呼吸功能障碍和过量活性氧产生，从而阻碍活性氧触发的Ca2+内流和RhoA/Rho激酶途径的激活。在体内，长期的有害冷刺激显著增加血管收缩和血压。膳食薄荷醇对TRPM8的激活抑制了血管活性氧的产生，血管收缩，并通过以TRPM8依赖的方式减弱过多的线粒体活性氧介导的RhoA/Rho激酶的激活来降低血压。薄荷醇的这些作用在血管紧张素ii诱导的高血压小鼠中得到进一步验证。长期饮食薄荷醇治疗并保护线粒体功能可能是一种非药物措施，可用于环境有害冷致高血压。
Environmental cold‐induced hypertension is common, but how to treat cold‐induced hypertension remains an obstacle. Transient receptor potential melastatin subtype 8 (TRPM8) is a mild cold‐sensing nonselective cation channel that is activated by menthol. Little is known about the effect of TRPM8 activation by menthol on mitochondrial Ca2+ homeostasis and the vascular function in cold‐induced hypertension. Primary vascular smooth muscle cells from wild‐type or Trpm8−/− mice were cultured. In vitro, we confirmed that sarcoplasmic reticulum–resident TRPM8 participated in the regulation of cellular and mitochondrial Ca2+ homeostasis in the vascular smooth muscle cells. TRPM8 activation by menthol antagonized angiotensin II induced mitochondrial respiratory dysfunction and excess reactive oxygen species generation by preserving pyruvate dehydrogenase activity, which hindered reactive oxygen species–triggered Ca2+ influx and the activation of RhoA/Rho kinase pathway. In vivo, long‐term noxious cold stimulation dramatically increased vasoconstriction and blood pressure. The activation of TRPM8 by dietary menthol inhibited vascular reactive oxygen species generation, vasoconstriction, and lowered blood pressure through attenuating excessive mitochondrial reactive oxygen species mediated the activation of RhoA/Rho kinase in a TRPM8‐dependent manner. These effects of menthol were further validated in angiotensin II–induced hypertensive mice. Long‐term dietary menthol treatment targeting and preserving mitochondrial function may represent a nonpharmaceutical measure for environmental noxious cold–induced hypertension.