“废气不废”:气体信号分子硫化氢的研究进展

内源性气体信号分子的发现开辟了"废气不废"的新思路。硫化氢(hydrogen sulfide,H2S)是继一氧化氮(nitric oxide,NO)和一氧化碳(carbon monoxide,CO)之后的气体信号分子家系新成员。近年来,人们对H2S的内源性生成、生物学效应及其机制,特别是其在心血管、神经、呼吸、内分泌等系统的疾病发生、发展过程中的病理生理学意义进行了广泛研究。本文综述了近年来H2S相关基础、临床以及药学研究方面的进展,包括H2S对细胞增殖和凋亡、炎症反应、血管新生及离子通道的调节作用,H2S在各种系统疾病发病中的调节作用,H2S供体及其在药学领域的研究进展。     

气体信号分子对心血管系统线粒体的作用

气体信号分子是由生物体内生成的、具有生物学效应的气态分子。目前已经发现一氧化氮(NO)、一氧化碳(CO)和硫化氢(H_2S) 3种气体信号分子。气体信号分子具有抗炎、抗氧化、抑制细胞凋亡、舒张血管、保护心脏等作用。线粒体在维持心肌细胞正常能量代谢中发挥重要作用,其功能紊乱会导致多种心血管系统疾病的发生。气体信号分子通过对线粒体的呼吸作用、线粒体的融合与分裂、线粒体自噬,以及活性氧生成等方面进行调控,介导线粒体功能,使心肌细胞维持正常生理功能。本文就3种气体信号分子对心血管系统线粒体的作用予以综述。     

内源性二氧化硫对心肌损伤的作用及机制

二氧化硫(sulfur dioxide,SO₂)是一种具有强烈刺激性气味的酸性气体，以往常被认为是有害物质。内源性SO₂是继一氧化氮(nitric oxide,NO)、一氧化碳(carbon monoxide,CO)和硫化氢(hydrogen sulfide,H₂S)之后的第四种气体信号分子，可以在心血管组织中内源性生成，并且在心血管系统调节中发挥着重要的生理和病理学作用。SO₂对心功能发挥剂量依赖性的负性肌力作用，其中三磷酸腺苷敏感钾通道参与其中。SO₂还能减轻各种有害刺激引起的心肌损伤，在心肌缺血-再灌注损伤和心肌肥厚中发挥重要作用，作用机制与SO₂的抑制炎症和抗氧化作用有关。此外，SO₂还可以抑制心肌细胞的凋亡和自噬。因此，内源性SO₂在维持心血管系统的稳态中发挥重要作用。本文将围绕内源性SO₂生成代谢、心血管生物学效应及对内源性SO₂/天冬氨酸氨基转移酶(asp...     

硫化氢在肺血管重塑中的调节机制及信号通路

以肺动脉压力进行增高为特征的肺动脉高压(PH)是临床上棘手的疾病之一,而肺血管重塑是导致肺动脉高压的关键环节。内源性硫化氢(H2S)是继一氧化氮和一氧化碳之后发现的第三种气体信号分子,具有多种生物效应,其作用也愈加受到关注。大量研究表明H2S可以调节肺血管重塑,与PH的发生及转归具有密切关系。本文主要集中阐述近年来H2S及其在PH的血管重塑中调节机制以及信号通路的新进展,旨在为PH的防治提供新的思路和启发。     

硫化氢对炎症和急危重症作用机制的研究进展

一直以来硫化氢（Hydrogensulfide,H2S）被认为是具有臭鸡蛋气味的有毒气体。关于H2S的研究主要集中在毒性方面,人接触H2S可导致如眼炎、化学性肺炎、肺水肿、上消化道不适,中枢神经系统等症状,甚至猝倒呈闪电样死亡[1]。20世纪90年代末,人们发现内源性H2S的存在。研究证实,H2S作为一种新型内源性气体信号分子,参与心血管、神经、呼吸、消化、内分泌及免疫系统等多个系统的病理生理过程。     

内源性H2S --一种新的气体信号分子

20世纪90年代中期,发现半胱氨酸代谢生成气体分子硫化氢（H2S）,对神经系统特别是海马的功能具有调节作用,并可以调节消化道和血管平滑肌的张力,而其作用特点有别于另外两种气体信号分子NO及CO,但H2S的信号转导途径一直未能阐明,直到最近研究证实,内源性H2S直接作用于KATP通道实现对血管的调节作用;而且可以刺激神经细胞cAMP水平增加,提高NMDA受体介导的突触后兴奋性电位,提高诱导海马长时程增强。越来越多的证明表明,内源性H2S是一种新的气体信号分子,对其研究是当前生物学领域的崭新课题,具有重要的理论和临床意义。     

硫化氢对抗脑缺血再灌注损伤的机制研究进展

硫化氢（H2S）是一种新型内源性气体信使分子,在许多生理和病理生理过程中,尤其在神经保护中,扮演重要角色,既是神经调节剂, 也是神经保护剂。近年来的研究发现,H2S对于脑缺血再灌注损伤具有积极的防治作用,它可通过抗氧化应激、抗炎及抗细胞凋亡等多个途径, 对脑缺血再灌注损伤起保护作用,具有良好的临床应用前景。简介脑内H2S生成途径,综述H2S在中枢神经系统中的生物学效应及其对脑 缺血再灌注损伤的保护作用与机制研究进展,以期为脑缺血再灌注损伤的临床防治提供新思路。     

外源性硫化氢与肾脏缺血再灌注

H2S是内源性气体信号分子,在治疗疾病方面有很大应用前景。肾脏是人体重要器官,具有诸多生理功能。肾缺血再灌注损伤时可导致严重的组织损伤或器官功能衰竭,本文就H2S在肾脏的缺血再灌注损伤中的作用做一综述。     

应激机体适应的心血管分子基础的相关研究

心血管系统是多种应激因素作用的首要靶器官,它在应激机体的适应调控中具有非常重要的作用,对其分子基础的认识才刚刚开始。应激机体适应的心血管分子基础涉及到一个复杂的细胞内调控网络和多种内源性物质。本文就信号分子、受体、细胞内信息传导因素、相关的应激基因、效应蛋白等以及之间的关系作了综述。     

硫化氢在血压调节中的作用

内源性硫化氢（H2S）是新近发现的第三种气体信号分子,它具有重要的生理意义。在心血管系统,它有舒张血管、降低血压、抑制血管平滑肌细胞增殖以及减轻血管重构等多种生物学效应。研究发现,硫化氢能直接作用于ATP敏感性钾通道实现对血管的调节作用;能通过作用于丝裂原激活蛋白激酶（MAPK）途径抑制平滑肌细胞增殖。现已证明,硫化氢还与高血压、肺动脉高压等疾病关系密切。     

S1P 信号通路：心血管疾病治疗的新靶点

1- 磷酸鞘氨醇是一种有生物活性的脂质代谢产物,具有调节细胞增殖、再生、迁移,细胞内钙离子移动,黏附分子表达以及激活单核细胞黏附内皮细胞等功效,在血管生理性再生及动脉粥样硬化斑块发生发展中发挥重要作用。1- 磷酸鞘氨醇在高密度脂蛋白中含量在所有脂蛋白中最高,其参与调节高密度脂蛋白的抗氧化、抗血栓、抗炎等效应,而这些反应与1- 磷酸鞘氨醇的生物学功能如血管发生、内皮保护、抑制平滑肌细胞迁移、心肌缺血再灌注损伤的保护等密切相关。对1- 磷酸鞘氨醇信号通路在心血管系统中的作用及以该通路为靶点的相关药物研究进展进行综述,为今后研究提供参考。     

嗜酸硫杆菌属硫氧化系统研究进展

硫化矿的酸溶解和化学氧化过程中(H 和Fe3 作用下,金属硫化矿中分解),伴随着硫元素转变成多聚硫S8或硫代硫酸盐的过程。对嗜酸硫杆菌属硫氧化过程的研究表明,胞外环状多聚硫S8可能通过细胞外膜蛋白巯基活化成线状-SnH后,被转运到细胞周质区域,进而被硫加双氧酶氧化成SO32-,活化过程中同时生成少量H2S;这些酶促反应不需要辅助因子参与,不释放电子。胞外硫代硫酸盐通过未知途径进入细胞周质。细胞周质中的SO32-主要经由亚硫酸-受体氧化还原酶氧化成SO42-,S2O32-可能经由硫代硫酸盐-辅酶Q氧化还原酶、硫代硫酸盐脱氢酶、连四硫酸盐水解酶等氧化为硫酸,少量H2S则经由硫化物-辅酶Q氧化还原酶氧化为多聚硫,后者再经由SO32-和S2O32-氧化生成最后产物SO42-。这些生物氧化过程释放的电子进入呼吸链参与产生细菌生长代谢所需的能量。然而,关于A.ferrooxidans硫氧化系统中各种硫化合物的酶催化氧化机制的研究仍很缺乏,胞内外硫化合物的转运机制、是否存在胞外酶催化氧化等仍然有待解决。另外,硫的型态和价态、酶催化反应的细胞微区域以及硫氧化系统中一些关键酶的分离及其表达基因的鉴定等问题都还有待进一步研究。基于对这些事实的分析,提出了一个嗜酸硫杆菌属硫氧化系统的模型。     

Regulation of cardiovascular cell function by hydrogen sulfide (H2S)

Since the discovery of endogenously‐produced hydrogen sulfide (H₂S) in various tissues, there has been an explosion of interest in H₂S as a biological mediator alongside other gaseous mediators, nitric oxide and carbon monoxide. The identification of enzyme‐regulated H₂S synthetic pathways in the cardiovascular system has led to a number of studies examining specific regulatory actions of H₂S. We review evidence showing that endogenously‐generated and exogenously‐administered H₂S exerts a wide range of actions in vascular and myocardial cells including vasodilator/vasoconstrictor effects via modification of the smooth muscle tone, induction of apoptosis and anti‐proliferative responses in the smooth muscle cells, angiogenic actions, effects relevant to inflammation and shock, and cytoprotection in models of myocardial ischemia‐reperfusion injury. Several molecular mechanisms of action of H₂S have been described. These include interactions of H₂S with NO, redox regulation of multiple signaling proteins and regulation of K_ATP channel opening. The gaps in our current understanding of precise mechanisms, the absence of selective pharmacological tools and the limited availability of H₂S measurement techniques for living tissues, leave many questions about physiological and pathophysiological roles of H₂S unanswered at present. Nevertheless, this area of investigation is advancing rapidly. We believe H₂S holds promise as an endogenous mediator controlling a wide range of cardiovascular cell functions and integrated responses under both physiological and pathological conditions and may be amenable to therapeutic manipulation. Copyright © 2010 John Wiley & Sons, Ltd.     

硫化氢在心血管保护过程中免疫炎症调节研究进展

硫化氢(hydrogen sulfide,H_2S)是一种无色、具有臭鸡蛋气味的气体,过去认为只是一种有毒的气体。近年来大量研究证实H_2S是继一氧化氮(nitric oxide,NO)和一氧化碳(carbon oxide,CO)后第三种内源性气体信号分子,同时,H_2S在心血管系统疾病发生、发展过程中起关键的调控作用,但其机制还不明确,已有报道主要通过抗凋亡、抗氧化、调节内皮一氧化氮合酶活性、促进血管新生等;而本文总结了H_2S在缺血性心脏病、动脉粥样硬化等心血管疾病中免疫炎症调节作用及其机制,从而为H_2S生物学功能以及相关心血管疾病的防治提供新的思路。     

The cardioprotective potential of hydrogen sulfide in myocardial ischemia/reperfusion injury (review)

Myocardial infarction is responsible for the majority of cardiovascular mortality and the pathogenesis of myocardial damage during and after the infarction involves reactive oxygen species. Serious efforts are under way to modulate the developing ischemia/reperfusion injury and recently the use of hydrogen sulfide (H2S) emerged as a new possibility. H2S has been best known for decades as a pungent toxic gas in contaminated environmental atmosphere, but it has now been recognized as a novel gasotransmitter in the central nervous and cardiovascular systems, similarly to nitric oxide (NO) and carbon monoxide (CO). This finding prompted the investigation of the potential of H2S as a cardioprotective agent and various in vitro and in vivo results demonstrate that H2S may be of value in cytoprotection during the evolution of myocardial infarction. Although several questions remain to be elucidated about the properties of this new gasotransmitter, increased H2S levels may have therapeutic potential in clinical settings in which ischemia/reperfusion injury is encountered. This review article overviews the current understanding of the effects of this exciting molecule in the setting of myocardial ischemia/reperfusion.     

1-磷酸鞘氨醇受体

1-磷酸鞘氨醇(sphingosine-1-phosphate,S1P)对动脉粥样硬化等心血管疾病的发生发展具有重要作用。最近研究发现S1P在不同细胞发挥的生物学效应由其受体(sphingosine-1-phosphate receptor,S1PR)介导,以S1PR及其信号机制为基础的研究及治疗策略成为新的研究热点。本文主要综述S1PR的功能、信号通路及对心血管疾病的影响,为心血管疾病的预防和诊疗提供新的靶点。     

Hippo信号通路与心血管发育及疾病调控

心血管疾病已成为中国乃至全球首位死亡原因,探索心血管系统发育及调控异常的原因及相关机制可以为心血管疾病的预防和治疗提供重要的科学依据。Hippo信号通路是新近发现的在调节器官大小、细胞增殖及凋亡、干细胞命运等方面具有重要功能的一条信号通路。Hippo信号通路的不同成分参与心脏血管的发育和心血管细胞增殖、分化等功能调控,影响损伤后修复及再生等过程,该通路调节异常可引起心血管疾病,如心梗、心肌肥大、血管内膜增生、动脉硬化等。本文综述了Hippo信号通路对心血管系统发育和疾病调控的相关研究及最新进展,以期为Hippo通路在心血管疾病的发病机制及临床转化研究提供潜在的理论基础。     

Hydrogen sulfide inhibits myocardial injury induced by homocysteine in rats

Hyperhomocysteinemia (HHcy) is a critical independent risk factor for cardiovascular diseases. However, to date, no satisfactory strategies to prevent HHcy exist. Since homocysteine (Hcy) and endogenous H₂S are both metabolites of sulfur-containing amino acids, we aimed to investigate whether a metabolic product of Hcy and H₂S, may antagonize in part the cardiovascular effects of Hcy. In the HHcy rat model injected subcutaneously with Hcy for 3 weeks, H₂S levels and the H₂S-generating enzyme cystathionine γ lyase (CSE) activity in the myocardium were decreased. The intraperitoneal injection of H₂S gas saturation solution significantly reduced plasma total Hcy (tHcy) concentration and decreased lipid peroxidation formation (i.e., lowered manodialdehyde and conjugated diene levels in myocardia and plasma). The activities of myocardial mitochondrial respiratory enzymes succinate dehydrogenase, cytochrome oxidase, and manganese superoxide dismutase, related to reactive oxygen species metabolism, were significantly dysfunctional in HHcy rats. The H₂S administration restored the level of enzyme activities and accelerated the scavenging of H₂O₂ and superoxide anion generated by Hcy in isolated mitochondria. The H₂S treatment also inhibited the expression of glucose-regulated protein 78, a marker of endoplasmic reticulum (ER) stress, induced by Hcy in vivo and in vitro. Thus, HHcy impaired the myocardial CSE/H₂S pathway, and the administration of H₂S protected the myocardium from oxidative and ER stress induced by HHcy, which suggests that an endogenous metabolic balance of sulfur-containing amino acids may be a novel strategy for treatment of HHcy.     

Nitric oxide synthase inhibition abrogates hydrogen sulfide-induced cardioprotection in mice

The cardioprotective property of hydrogen sulfide (H(2)S) is recently reported. However, cellular signaling cascades mediated by H(2)S are largely unclear. This study was undertaken to explore the molecular mechanism of H(2)S-induced cardioprotection in mouse heart by utilizing in vivo model of cardiac injury. We report here that intraperitoneal administration of sodium hydrogen sulfide (NaHS, 50 μmol kg(-1 )day(-1) for 2 days), a H(2)S donor, significantly (P ≤ 0.05) increased nitric oxide levels in serum as well as myocardium without any sign of myocardial injury. Typical characteristics of myocardial injury induced by isoproterenol (ISO) administration was significantly (P ≤ 0.05) abrogated by NaHS administration as evidenced from reduction in elevated thiobarbituric acid reactive substances (TBARS) and normalization of glutathione (GSH), glutathione peroxidase, superoxide dismutase (SOD), and catalase activity. Further, decrease in TNF-α expression and improvement in myocardial architecture was also observed. However, co-administration of N-nitro-L-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor, and Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor along with NaHS and ISO abrogated the beneficial effect of H(2)S differentially. Inhibition of NOS significantly (P ≤ 0.05) increased serum creatine kinase, lactate dehydrogenase, serum glutamic oxaloacetic transaminase activity and myocardial TBARS, along with significant (P ≤ 0.05) reduction of myocardial GSH, SOD, and catalase. This was followed by increase in TNF-α expression and histopathological changes. Our results revealed that H(2)S provides myocardial protection through interaction with NOS and COX-2 pathway and inhibition of NOS completely abrogates the hydrogen sulfide-induced cardioprotection in mice.