Archer Stephen L, Gomberg-Maitland Mardi, Maitland Michael L, Rich Stuart, Garcia Joe G N, Weir E Kenneth
University of Chicago, Section of Cardiology, IL 60637, USA.
Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H570-8. doi: 10.1152/ajpheart.01324.2007. Epub 2007 Dec 14.
Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by vascular obstruction and right ventricular failure. Although the fundamental cause remains elusive, many predisposing and disease-modifying abnormalities occur, including endothelial injury/dysfunction, bone morphogenetic protein receptor-2 gene mutations, decreased expression of the O(2)-sensitive K(+) channel (Kv1.5), transcription factor activation [hypoxia-inducible factor-1alpha (HIF-1alpha) and nuclear factor-activating T cells], de novo expression of survivin, and increased expression/activity of both serotonin transporters and platelet-derived growth factor receptors. Together, these abnormalities create a cancerlike, proliferative, apoptosis-resistant phenotype in pulmonary artery smooth muscle cells (PASMCs). A possible unifying mechanism for PAH comes from studies of fawn-hooded rats, which manifest spontaneous PAH and impaired O(2) sensing. PASMC mitochondria normally produce reactive O(2) species (ROS) in proportion to P(O2). Superoxide dismutase 2 (SOD2) converts intramitochondrial superoxide to diffusible H(2)O(2), which serves as a redox-signaling molecule, regulating pulmonary vascular tone and structure through effects on Kv1.5 and transcription factors. O(2) sensing is mediated by this mitochondria-ROS-HIF-1alpha-Kv1.5 pathway. In PAH and cancer, mitochondrial metabolism and redox signaling are reversibly disordered, creating a pseudohypoxic redox state characterized by normoxic decreases in ROS, a shift from oxidative to glycolytic metabolism and HIF-1alpha activation. Three newly recognized mitochondrial abnormalities disrupt the mitochondria-ROS-HIF-1alpha-Kv1.5 pathway: 1) mitochondrial pyruvate dehydrogenase kinase activation, 2) SOD2 deficiency, and 3) fragmentation and/or hyperpolarization of the mitochondrial reticulum. The pyruvate dehydrogenase kinase inhibitor, dichloroacetate, corrects the mitochondrial abnormalities in experimental models of PAH and human cancer, causing a regression of both diseases. Mitochondrial abnormalities that disturb the ROS-HIF-1alpha-Kv1.5 O(2)-sensing pathway contribute to the pathogenesis of PAH and cancer and constitute promising therapeutic targets.
肺动脉高压（PAH）是一种以血管阻塞和右心室衰竭为特征的致命综合征。尽管其根本病因仍不明确，但会出现许多易患因素和疾病修饰异常，包括内皮损伤/功能障碍、骨形态发生蛋白受体-2基因突变、氧敏感钾通道（Kv1.5）表达降低、转录因子激活[缺氧诱导因子-1α（HIF-1α）和核因子活化T细胞]、生存素的从头表达以及5-羟色胺转运体和血小板衍生生长因子受体的表达/活性增加。这些异常共同在肺动脉平滑肌细胞（PASMCs）中产生一种类似癌症的增殖、抗凋亡表型。PAH的一种可能的统一机制来自对淡黄带帽大鼠的研究，这些大鼠表现出自发性PAH和氧感应受损。PASMC线粒体通常根据氧分压（P(O2)）产生反应性氧物种（ROS）。超氧化物歧化酶2（SOD2）将线粒体内的超氧化物转化为可扩散的过氧化氢（H(2)O(2)），后者作为一种氧化还原信号分子，通过对Kv1.5和转录因子的作用来调节肺血管张力和结构。氧感应由这种线粒体-ROS-HIF-1α-Kv1.5途径介导。在PAH和癌症中，线粒体代谢和氧化还原信号传导可逆性紊乱，产生一种假性缺氧氧化还原状态，其特征是在常氧条件下ROS减少、代谢从氧化向糖酵解转变以及HIF-1α激活。三种新发现的线粒体异常破坏了线粒体-ROS-HIF-1α-Kv1.5途径：1）线粒体丙酮酸脱氢酶激酶激活，2）SOD2缺乏，3）线粒体网状结构的碎片化和/或超极化。丙酮酸脱氢酶激酶抑制剂二氯乙酸可纠正PAH实验模型和人类癌症中的线粒体异常，使两种疾病都出现消退。干扰ROS-HIF-1α-Kv1.5氧感应途径的线粒体异常促成了PAH和癌症的发病机制，并构成了有前景的治疗靶点。
