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.
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Mitochondria, Ca2+, and reactive oxygen species (ROS) are each integral to vascular function and are thought to be involved in the development of hypertension. Pyruvate dehydrogenase (PDH) and several complexes of electron transport have been reported to be Ca2+ dependent.
8 Increased physiological levels of mitochondrial Ca2+ uptake is the coordinated upregulation of the entire oxidative phosphorylation activity.
9 PDH is one of the key dehydrogenases of the tricarboxylic acid cycle, the activity of which is blunted by Angiotensin II (Ang II) by increasing PDH phosphorylation in vascular smooth muscle cells (VSMCs).
10 Meanwhile, mitochondrial matrix Ca2+ overload impairs mitochondrial function and leads to ROS generation.
11 Excessive mitochondrial ROS is implicated in the development of vascular dysfunction.
12 Ang II–induced mitochondrial ROS generation promotes Ca2+ influx and, subsequently, contraction in arterial smooth muscle.
13 Under pathological conditions of cytosolic Ca2+ overload, mitochondria are capable of taking up large amounts of Ca2+.
14 This vicious cycle might be an important factor contributing to the excess mitochondrial ROS production in VSMCs. Indeed, ROS‐mediated upregulation of the RhoA/Rho kinase pathway promotes vasoconstriction and contributes to high blood pressure (BP).
15 It is worth investigating whether ameliorating mitochondrial dysfunction disrupts this vicious cycle and attenuates vascular dysfunction in hypertension.
Currently, application of ROS scavengers, which eliminate the total levels of tissue and cellular ROS, has not generally achieved favorable effects on ameliorating cardiovascular diseases.
16 Using mitochondria‐targeted antioxidants to alleviate mitochondrial oxidative stress might efficiently attenuate hypertension.
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To further examine the effect of TRPM8 activation on mitochondrial ROS mediated RhoA/Rho kinase activation, we performed studies in primary cultured aortic VSMCs. It showed that mitochondrial‐targeting ROS scavenger MitoTEMPO efficiently inhibited Ang II–induced RhoA/Rho kinase pathway activation (Figure
6G through
through6J).6J). Menthol treatment similarly inhibited the activation of RhoA pathway in VSMCs from WT but not Trpm8−/− mice (Figure
6G through
through6J).6J). These results suggest that the activation of TRPM8 by menthol prevents excessive mitochondrial ROS‐mediated RhoA/Rho kinase pathway activation in the vasculature from CIH.