Potential role of mitochondrial superoxide decreasing ferrochelatase and heme in coronary artery soluble guanylate cyclase depletion by angiotensin II
Potential role of mitochondrial superoxide decreasing ferrochelatase and heme in coronary artery soluble guanylate cyclase depletion by angiotensin II
复制标题
DOI：
10.1152/ajpheart.00859.2015
复制
发表时间：
2016-06-01
影响因子：
4.8
通讯作者：
Wolin, Michael S.
中科院分区：
文献类型：
--
作者：
Patel, Dhara;Alhawaj, Raed;Wolin, Michael S.
可溶性鸟苷酸环化酶（sGC）血红素的氧化促进一氧化氮（NO）调节的丧失和sGC的消耗。我们假设，血管紧张素II（ANG II）刺激线粒体超氧化物的1型受体可以作为一个潜在的抑制剂血红素生物合成的亚铁螯合酶，这可能会降低血管的反应性NO消耗sGC。这些过程进行了研究，在24小时的类器官培养模型的牛冠状动脉（BCA）与0.1 μ M ANG II。与ANG II的BCA治疗增加线粒体超氧化物，耗尽线粒体超氧化物歧化酶（SOD 2），亚铁螯合酶，细胞色素氧化酶亚基4，和sGC，与损伤的松弛NO。这些过程被衰减的类器官培养与8-溴-cGMP和/或δ-氨基乙酰丙酸（sGC的刺激原卟啉IX生成和血红素生物合成）。用线粒体基质超氧化物清除剂Mito-TEMPOL进行的类器官培养也减弱了ANG II引起的亚铁螯合酶消耗和对NO的松弛损失，而用线粒体外超氧化物清除剂Tempol进行的类器官培养减弱了ANG II对NO的松弛损失，但没有减弱亚铁螯合酶消耗，提示细胞内超氧化物可能是NO对sGC调控丧失的起始因素。（但不是过氧化氢酶）表明sGC表达可能对由ANG II通过增加线粒体超氧化物破坏亚铁螯合酶活性引起的血红素消耗非常敏感。此外，cGMP依赖性激活蛋白激酶G似乎减弱这些ANG II刺激的过程，通过防止SOD 2耗竭和线粒体和线粒体外超氧化物的增加。
Oxidation of the soluble guanylate cyclase (sGC) heme promotes loss of regulation by nitric oxide (NO) and depletion of sGC. We hypothesized that angiotensin II (ANG II) stimulation of mitochondrial superoxide by its type 1 receptor could function as a potential inhibitor of heme biosynthesis by ferrochelatase, and this could decrease vascular responsiveness to NO by depleting sGC. These processes were investigated in a 24-h organoid culture model of bovine coronary arteries (BCA) with 0.1 mu M ANG II. Treatment of BCA with ANG II increased mitochondrial superoxide, depleted mitochondrial superoxide dismutase (SOD2), ferrochelatase, and cytochrome oxidase subunit 4, and sGC, associated with impairment of relaxation to NO. These processes were attenuated by organoid culture with 8-bromo-cGMP and/or delta-aminolevulinic acid (a stimulator of sGC by protoporphyrin IX generation and heme biosynthesis). Organoid culture with Mito-TEMPOL, a scavenger of mitochondrial matrix superoxide, also attenuated ANG II-elicited ferrochelatase depletion and loss of relaxation to NO, whereas organoid culture with Tempol, an extramitochondrial scavenger of superoxide, attenuated the loss of relaxation to NO by ANG II, but not ferrochelatase depletion, suggesting cytosolic superoxide could be an initiating factor in the loss of sGC regulation by NO. The depletion of cytochrome oxidase subunit 4 and sGC (but not catalase) suggests that sGC expression may be very sensitive to depletion of heme caused by ANG II disrupting ferrochelatase activity by increasing mitochondrial superoxide. In addition, cGMP-dependent activation of protein kinase G appears to attenuate these ANG II-stimulated processes through both preventing SOD2 depletion and increases in mitochondrial and extramitochondrial superoxide.