Risbano Michael G, Gladwin Mark T
Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Handb Exp Pharmacol. 2013;218:315-49. doi: 10.1007/978-3-642-38664-0_13.
All forms of WHO Group 1 PAH share a progressive and complex vasculopathy. At the center of this derangement lies the pulmonary vascular endothelium, which plays a crucial role in maintaining a delicate and precise balance of opposing vasoconstricting and vasodilating forces. In PAH, endothelial cell damage and dysfunction alter vascular homeostasis in favor of vasoconstriction. There is evidence of increased expression and activity in the vasoconstrictor and mitogen endothelin-1 signaling system and a decreased production of the potent vasodilator prostacyclin. These pathways have been a major focus of FDA approved PAH-specific therapies. Beyond these pathways, there is the dysfunction within the endothelial nitric oxide (NO) synthase signaling pathway and dysregulation of reactive oxygen and nitrogen species (ROS) that contribute to the pathogenesis of PAH. The dysregulation of vasodilator systems in PAH in large part involves the NO pathway, with almost every step subject to impairments. This includes a reduction in endothelial NO synthase function (eNOS), the enzymatic "uncoupling" of eNOS, increased scavenging of NO by superoxide and cell-free hemoglobin, the elaboration of endogenous competitive inhibitors of eNOS (ADMA), and the oxidation of the NO target, soluble guanylyl cyclase. The dysregulation of NO signaling pathways occurs in the setting of parallel upregulation of vascular oxidases that generate ROS. Enzymatic sources of ROS in PH that have been identified include the NAPDPH oxidases 1, 2, and 4, xanthine oxidase, uncoupled eNOS, and complex III of the mitochondrial electron transport chain. Superoxide produced from these sources reacts with NO to form the reactive nitrogen species peroxynitrate, further diverting bioavailable NO to more injuries species. In PAH, this upstream dysregulation of ROS/NO redox homeostasis severely impairs vascular tone and contributes to the pathological activation of mitogenic pathways, leading to cellular proliferation and obliteration of the pulmonary vasculature. Therapeutic strategies are being evaluated that target the associated dysregulated redox equilibrium and endothelial dysfunction in PAH. Therapeutic interventions reviewed in this chapter include NO donor or NO generating drugs, therapies that recouple eNOS or directly increase cGMP levels via inhibition of phosphodiesterase 5 or stimulation of soluble guanylyl cyclase, and therapies that inhibit vascular oxidases or scavenge ROS.
世界卫生组织第1组肺动脉高压（PAH）的所有形式都具有进行性和复杂性血管病变。这种紊乱的核心是肺血管内皮，它在维持血管收缩和舒张力量的微妙而精确的平衡中起着关键作用。在PAH中，内皮细胞损伤和功能障碍改变了血管稳态，有利于血管收缩。有证据表明，血管收缩剂和有丝分裂原内皮素-1信号系统的表达和活性增加，而强效血管舒张剂前列环素的产生减少。这些途径一直是美国食品药品监督管理局（FDA）批准的PAH特异性疗法的主要重点。除了这些途径，内皮型一氧化氮（NO）合酶信号通路功能障碍以及活性氧和氮物种（ROS）失调也参与了PAH的发病机制。PAH中血管舒张系统的失调在很大程度上涉及NO途径，几乎每个步骤都受到损害。这包括内皮型NO合酶功能（eNOS）降低、eNOS的酶促“解偶联”、超氧化物和游离血红蛋白对NO的清除增加、eNOS内源性竞争性抑制剂（ADMA）的产生以及NO靶点可溶性鸟苷酸环化酶的氧化。NO信号通路的失调发生在产生ROS的血管氧化酶平行上调的背景下。已确定的PH中ROS的酶源包括NADPH氧化酶1、2和4、黄嘌呤氧化酶、解偶联的eNOS以及线粒体电子传递链的复合物III。这些来源产生的超氧化物与NO反应形成活性氮物种过氧亚硝酸盐，进一步将生物可利用的NO转移到更多的损伤物种。在PAH中，ROS/NO氧化还原稳态的这种上游失调严重损害血管张力，并导致有丝分裂途径的病理激活，从而导致细胞增殖和肺血管闭塞。目前正在评估针对PAH中相关失调的氧化还原平衡和内皮功能障碍的治疗策略。本章中综述的治疗干预措施包括NO供体或产生NO的药物、使eNOS重新偶联或通过抑制磷酸二酯酶5或刺激可溶性鸟苷酸环化酶直接增加cGMP水平的疗法，以及抑制血管氧化酶或清除ROS的疗法。
