Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease.
Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease.
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DOI：
10.1161/circulationaha.110.981738
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发表时间：
2011-05-24
期刊：
影响因子：
37.8
通讯作者：
Evgenov OV
中科院分区：
文献类型：
--
作者：
Stasch JP;Pacher P;Evgenov OV
作为一氧化氮(NO)信号通路的关键酶，可溶性鸟苷环化酶(SGC)作为心肺疾病的治疗靶点正受到越来越多的关注，目前有几种sGC激动剂正在临床开发中。在NO与sGC上的假体血红素基团结合时，该酶催化合成第二信使cGMP，该信使产生血管松弛，并通过一些下游机制抑制血管平滑肌增殖、白细胞募集和血小板聚集。1、2 NO和cGMP信号受损参与了心血管疾病的发生，包括全身动脉和肺动脉高压(PH)、冠状动脉疾病、外周血管疾病(包括勃起功能障碍)和动脉粥样硬化。针对NO信号通路的1，3-5种有机硝酸盐用于治疗心血管疾病已有150年的历史。最近，吸入吸入气态NO已被批准用于治疗新生儿持续性PH。3、6尽管如此，这些药物仍有几个重要的局限性。心血管疾病与对一氧化氮和有机硝酸盐的抗药性有关。7这可能是由于氧化应激导致sGC上人工血红素氧化还原状态的改变(从亚铁到铁)，从而削弱了血红素与酶的结合，使sGC对1、8号没有反应。此外，有机硝酸盐的长期疗效受到耐受性发展的限制。9一氧化氮也可能有许多细胞毒性作用，主要归因于反应性氧化剂过氧亚硝酸盐(由NO与超氧化物的扩散控制反应形成)。过氧亚硝酸盐与蛋白质和脂质相互作用，改变细胞信号，扰乱线粒体功能，破坏DNA，最终导致细胞功能障碍和/或死亡。3由于NO的有益作用似乎是通过sGC-cGMP依赖的下游机制介导的，而其大部分有害作用是独立发生的，11最近的努力集中在寻找可以直接靶向sGC-cGMP信号的药理药物。直接作用于sGC的化合物可根据其作用方式分为两类：sGC刺激剂和sGC激活剂。刺激剂通过稳定亚硝胺复合体从而维持酶的活性构型，使sGC对低水平的生物可用NO敏感；它们也可以在没有11号、12号的情况下增加sGC的活性，它们的作用依赖于还原的(铁)人工血红素的存在。相比之下，sGC激活剂在sGC处于氧化状态或最终处于无血红素状态时优先有效地激活sGC(图1)。血红素基团氧化sGC导致其从酶上解离，产生NO不敏感的sGC，仅具有基本活性。18在高血压和高脂血症的动物模型中，以及在某些心血管疾病和人类2型糖尿病中，氧化或半血sGC水平升高。19、20最近，在一项对只表达无血红素版本的酶的转基因小鼠的研究中，证明了高水平无血红素sGC的有害影响。这些小鼠患有全身性高血压，对NO的平滑肌松弛反应丧失，寿命缩短。因此，这两类sGC激动剂可能在不同的疾病组中有用，这取决于与NO(sGC激动剂)的协同作用相对于在与氧化…相关的条件下优先发挥作用的能力的相对重要性。
Soluble guanylate cyclase (sGC), a key enzyme of the nitric oxide (NO) signaling pathway, is attracting rapidly growing interest as a therapeutic target in cardiopulmonary disease, with several sGC agonists currently in clinical development. On binding of NO to a prosthetic heme group on sGC, the enzyme catalyzes synthesis of the second messenger cGMP, which produces vasorelaxation and inhibits smooth muscle proliferation, leukocyte recruitment, and platelet aggregation through a number of downstream mechanisms. 1, 2 Impaired NO and cGMP signaling has been implicated in the pathogenesis of cardiovascular disease, including systemic arterial and pulmonary hypertension (PH), coronary artery disease, peripheral vascular disease (including erectile dysfunction), and atherosclerosis. 1, 3–5 Organic nitrates that target the NO signaling pathway have been used to treat cardiovascular disease for 150 years. More recently, gaseous NO administered by inhalation has been approved for the treatment of persistent PH of the newborn. 3, 6 These agents nonetheless have several important limitations. Cardiovascular disease is associated with resistance to NO and organic nitrates. 7 This may be due to the oxidative stress–induced alteration of the redox state of the prosthetic heme on sGC (from ferrous to ferric) that weakens the binding of heme to the enzyme and renders sGC unresponsive to NO. 1, 8 Furthermore, the long-term efficacy of organic nitrates is limited by the development of tolerance. 9 Nitric oxide may also have numerous cytotoxic effects, mostly attributed to the reactive oxidant peroxynitrite (formed from the diffusion-controlled reaction of NO with superoxide). 3, 10 Peroxynitrite interacts with proteins and lipids, altering cellular signaling, disrupting mitochondrial function, and damaging DNA, which can eventually culminate in cellular dysfunction and/or death. 3 Because the beneficial effects of NO appear to be mediated through the sGC-cGMP–dependent downstream mechanisms, whereas most of its detrimental effects occur independently, 11 recent efforts have centered on identifying pharmacological agents that could target sGC-cGMP signaling directly. Compounds that act directly on sGC can be divided into 2 categories based on their modes of action: sGC stimulators and sGC activators. Stimulators sensitize sGC to low levels of bioavailable NO by stabilizing the nitrosylheme complex and thus maintaining the enzyme in its active configuration; they can also increase sGC activity in the absence of NO. 11, 12 Their action is dependent on the presence of a reduced (ferrous) prosthetic heme. 13–15 In contrast, sGC activators preferentially and effectively activate sGC when it is in an oxidized or, finally, a heme-free state (Figure 1). 11, 16, 17 Oxidation of the heme group on sGC results in its dissociation from the enzyme and the generation of NO-insensitive sGC, with only basal activity. 18 Levels of oxidized or hemefree sGC are increased in animal models of hypertension and hyperlipidemia, as well as in certain cardiovascular diseases and type 2 diabetes mellitus in humans. 19, 20 The detrimental effects of high levels of heme-free sGC were recently demonstrated in a study of genetically modified mice that express only the heme-free version of the enzyme. The mice had systemic hypertension with a loss of smooth muscle relaxation responses to NO and a shortened lifespan. 21 The 2 categories of sGC agonists may thus have utility in different groups of diseases, depending on the relative importance of synergistic action with NO (sGC stimulators) compared with the ability to act preferentially in conditions associated with oxidative …