高血压时TRPC3激活致单核细胞线粒体功能障碍的机制

Reactive Oxidative stress (ROS) mediated by monocytes in hypertension is the initial step of atherosclerotic lesions, transient receptor potential channel canonical type (TRPC3) activation was associated with activation of monocyte. But it is not clear if the TRPC3 activation mediated by increased intracellular calcium would lead to increased production of ROS. Other studies have found that TRPC activation can promote the mitochondrial membrane permeability transition pore (mPTP) opening, increasing production of ROS.Our study shown that increased migration of monocytes in essential hypertension is associated with increased TRPC3, which related to increased systolic blood pressure and inflammatory factor. We hypothesis that increased TRPC3 mediated by activation of Ca2+ influx increased, through the regulation of Bcl-2, HKs and Akt signal pathway, leading to increased mitochondrial calcium, make mPTP open abnormal, increased generation of ROS, promote the development of atherosclerosis in hypertension. This study intends to genetically hypertensive rats as objects, make sure that how to mediate monocyte increased mitochondrial calcium induced mechanism of mPTP open abnormal when TRPC3 activation in hypertension, angiotensin II receptor blockers regulation of mitochondrial HKs against the ROS role. It has important significance for prevention and treatment of atherosclerosis in hypertension.

高血压时单核细胞介导的氧化应激(ROS)是动脉粥样病变的始动环节，瞬时受体电位通道3（TRPC3）激活与单核细胞活化有关。但尚不清楚TRPC3激活是否调控线粒体钙致ROS生成增加。研究报道TRPC激活能促进线粒体膜通透性转移孔(mPTP)开放, ROS生成增加。我们前期研究发现高血压时单核细胞TRPC3激活介导钙内流增加促进单核细胞迁移，与收缩压及炎症因子增加有关。为此，我们提出高血压时单核细胞TRPC3激活介导细胞内Ca2+增加，通过调控Bcl-2、HKs和Akt信号通路，导致线粒体钙增加，mPTP开放异常ROS生成增加，促进高血压发展为动脉粥样硬化的假说。本研究拟以遗传性高血压大鼠为研究对象，阐明高血压时TRPC3激活介导单核细胞线粒体钙增加致mPTP开放异常的机制，探讨血管紧张素II受体阻断剂能否通过调控线粒体HKs对抗ROS生成的作用，研究对高血压动脉粥样病变的防治有重要意义。

我们既往研究发现高血压时单核细胞瞬时受体电位通道（TRPC3）上调，介导的钙内流增加与收缩压增加有关；高血压时单核细胞迁移增加与TRPC3介导细胞内[Ca2+]i增加有关。本研究应用高血压动物模型和血管紧张素II诱导的高血压动物模型及TRPC3-/-模型等，我们发现与WKY相比较，SHR大鼠胞浆的TRPC3表达增加87%，线粒体TRPC3表达增加97%，siRNA-TRPC3敲减TRPC3或替米沙坦可抑制H2O2上调TRPC3表达的作用，且减少H2O2诱导的钙内流。抑制TRPC3可逆转H2O2的作用减少ROS生成。长期替米沙坦干预能显著抑制SHR单核细胞线粒体呼吸功能及氧消耗率，与替米沙坦上调己糖激酶HKI/HKII表达有关。我们的研究阐明高血压时TRPC3激活介导单核细胞线粒体的钙增加ROS生成的机制，揭示血管紧张素II受体阻断剂对单核细胞mPTP、膜电位等的作用，及线粒体ATP合酶复合体和HKI、HKII等调控线粒体功能的关键酶的作用。本研究的重要结果为发现与血压正常的WKY相比较，高血压时SHR线粒体的TRPC3表达增强，TRPC3激活介导单核细胞线粒体钙摄取增加，激活线粒体膜孔蛋白P70、ATP合酶复合体和和HKI、HKII使单核细胞mPTP开放，ROS生成增加。本研究为高血压动脉粥样早期病变的防治提供理论依据。