内源性硫化氢在心血管系统中的作用

内源性硫化氢是新近发现的第三个气体信使分子,在心血管系统,具有舒张血管、抑制血管平滑肌细胞增殖、心肌负性肌力等多种生物学效应,并在多种心血管疾病的发生发展中发挥一定作用。本文就硫化氢对心血管作用的最新研究进展作一综述。     

硫化氢与心血管疾病研究进展

硫化氢是继内源性气体分子一氧化氮和一氧化碳被证实为信号分子后,发现的又一种新的气体信号分子,它广泛地参与了神经、心血管和消化等系统的生理功能调节。在心血管系统,硫化氢主要由胱硫醚γ裂解酶催化合成,参与了血管张力、心肌收缩力、肺动脉高压、动脉粥样硬化、血流动力学改变以及心肌损伤的调节,并与多种心血管疾病相关。     

硫化氢与心血管系统疾病

硫化氢是一种新发现的内源性气体信号分子,目前已知其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,舒张血管和抑制平滑肌的增殖,在呼吸系统及炎症反应中都具有重要调节作用。近几年的基础研究表明,硫化氢参与了心血管系统正常生理功能的调控和病理生理过程,并与多种心血管系统疾病密切相关。     

硫化氢与高血压关系的研究进展

硫化氢是继一氧化氮与一氧化碳之后的新型气体信号分子,是一种强抗氧化剂及血管舒张因子[1]。过去人们一直致力研究它的毒性作用,直到20世纪90年代才逐步发现硫化氢在神经、心血管、消化和内分泌等系统中具有特定调节作用,参与机体多种病理生理过程。多项研究表明硫化氢参与高血压的发病且有对     

硫化氢：动脉粥样硬化研究新靶点

硫化氢是继一氧化氮和一氧化碳之后又一新的具有心血管调节功能的内源性气体信号分子。硫化氢能够通过保护血管内皮、抑制血管平滑肌细胞增殖和泡沫细胞的形成来抑制动脉粥样硬化的发展,硫化氢的这种保护作用是通过抗炎症、抗氧化应激等机制实现的。因此,硫化氢有望成为一种新的抗动脉粥样硬化作用的药物研发靶点。     

内源性硫化氢在心血管系统中的作用与意义

内源性硫化氢是新近发现的继一氧化氮和一氧化碳的第三类气体信号分子，具有舒张血管、降低血压、抑制血管平滑肌细胞增殖、心肌负性肌力等多种生物学效应，并在动脉粥样硬化、高血斥、心肌缺血等多种心血管疾病的发生发展中具有重要的病理生理意义。本文仅就内源性硫化氢的生化特性，在心血管系统的生理作用、作用机制及病理生理意义进行综述。     

硫化氢对心血管系统作用的研究进展

内源性硫化氢（H2S）是新近发现的第3个气体信使分子,在心血管系统,具有舒张血管、抑制血管平滑肌细胞增殖、心肌负性肌力等多种生物学效应,同时外源性H2S具有抑制细胞氧化磷酸化功能,具有保护心肌,防止缺血/再灌注损伤和保护移植供心等多种功能。本文就H2S对心血管作用的最新研究进展作一综述。     

气体信号分子硫化氢与高血压

<正> 硫化氢过去一直被认为是毒性气体,它的生理作用首先发现于1989年。进一步研究发现,由半胱氨酸代谢生成的气体分子硫化氢,在神经系统、消化系统和心血管系统均有重要生理作用。现已证明,在心血管系统中,硫化氢与高血压、肺动脉高压等关系密切。1 硫化氢的生物学特性     

内源性气体信号分子硫化氢对心血管系统离子通道的作用

硫化氢(H2S)为一种新的气体信号转导分子,其广泛存在于人体各种组织中。H2S对心血管系统具有重要的生理学效应,目前发现,其可作用于心血管系组织中离子通道,包括最重要的KKTP及L-Ca2 、TRRAI等通道有着开放或者关闭作用,参与了保护心脏、舒张血管等过程。本文就H2S对离子通道的作用简要综述。     

内源性气体信号分子硫化氢对心血管系统离子通道的作用

硫化氢(H2S)为一种新的气体信号转导分子,其广泛存在于人体各种组织中。H2S对心血管系统具有重要的生理学效应,目前发现,其可作用于心血管系组织中离子通道,包括最重要的KKTP及L-Ca2+、TRRAI等通道有着开放或者关闭作用,参与了保护心脏、舒张血管等过程。本文就H2S对离子通道的作用简要综述。     

气体信使硫化氢在大鼠肾血管性高血压中的调节作用

目的探讨硫化氢体系在肾血管性高血压形成及发展中的变化和作用。方法成年的雄性Wistar大鼠28只,随机分为对照组7只、双肾一夹组(two-kidney,one-clip,2KIC组)7只、2KIC+硫氢化钠(硫氢化钠为外源性硫化氢供者)组8只、假手术组6只,其中2KIC+硫氢化钠组每天腹腔注射硫氢化钠(56μmol/kg),对照组、2KIC组及假手术组注射相同剂量的生理盐水。相同条件饲养4周,4周后处死,检测血浆硫化氢水平,双肾硫化氢合酶的活性,血管紧张素Ⅱ,左心与全心重量比,光学显微镜下观察肾的显微结构变化。结果术后4周,2KIC组尾动脉压显著高于假手术组及2KIC+硫氢化钠组;2KIC组的血管紧张素Ⅱ显著高于假手术组和对照组;左心室与全心重量比值2KIC组高于对照组和假手术组;肾内硫化氢合酶的活性及血浆中硫化氢的含量2KIC组显著低于假手术组及对照组,2KIC+硫氢化钠组高于2KIC组。结论肾血管性高血压大鼠硫化氢体系受到严重抑制,可能是肾性高血压形成的重要因素,外源性的给予硫化氢供者有助于缓解高血压的形成。     

Cystathionine gamma-lyase-deficient smooth muscle cells exhibit redox imbalance and apoptosis under hypoxic stress conditions

BACKGROUND:

Hydrogen sulphide (H₂S) has recently emerged as a novel and important gasotransmitter in the cardiovascular system, where it is generated mainly by cystathionine gamma-lyase (CSE). Abnormal metabolism and functions of the CSE/H₂S pathway have been linked to various cardiovascular diseases including atherosclerosis and hypertension. An important role for H₂S in regulating the balance between cellular growth and death has been demonstrated whereby inhibition of the endogenous CSE/H₂S pathway results in greater apoptosis of vascular smooth muscle cells (SMCs). H₂S is increasingly recognized as a critical regulator of vascular integrity, but its role in SMCs during hypoxia has not been explored in a model of CSE deficiency.

METHODS:

Cell viability, apoptosis, redox status and mitochondrial activity in hypoxia-exposed (12 h at 1% O₂) SMCs derived from the mesenteric artery of CSE-knockout (CSE-KO) mice were analyzed. These were compared with those from CSE-wild-type (CSE-WT) mice.

RESULTS:

CSE-KO cells exhibited redox imbalance and aberrant mitochondrial activity versus CSE-WT cells, indicating an essential regulatory role for the endogenous CSE/H₂S pathway on SMC function. CSE-KO cells were also more susceptible to hypoxia-induced cell death, indicating a critical contribution of endogenous CSE/H₂S pathway to the protective hypoxia stress response.

CONCLUSION:

These findings support the concept that H₂S is a crucial regulator of vascular homeostasis, the deficiency of which is associated with various pathologies, and provide further evidence that H₂S is a potent vasculoprotectant.     

Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production

Although many types of ancient bacteria and archea rely on hydrogen sulfide (H(2)S) for their energy production, eukaryotes generate ATP in an oxygen-dependent fashion. We hypothesize that endogenous H(2)S remains a regulator of energy production in mammalian cells under stress conditions, which enables the body to cope with energy demand when oxygen supply is insufficient. Cystathionine γ-lyase (CSE) is a major H(2)S-producing enzyme in the cardiovascular system that uses cysteine as the main substrate. Here we show that CSE is localized only in the cytosol, not in mitochondria, of vascular smooth-muscle cells (SMCs) under resting conditions, revealed by Western blot analysis and confocal microscopy of SMCs transfected with GFP-tagged CSE plasmid. After SMCs were exposed to A23187, thapsigargin, or tunicamycin, intracellular calcium level was increased, and CSE translocated from the cytosol to mitochondria. CSE was coimmunoprecipitated with translocase of the outer membrane 20 (Tom20) in mitochondrial membrane. Tom20 siRNA significantly inhibited mitochondrial translocation of CSE and mitochondrial H(2)S production. The cysteine level inside mitochondria is approximately three times that in the cytosol. Translocation of CSE to mitochondria metabolized cysteine, produced H(2)S inside mitochondria, and increased ATP production. Inhibition of CSE activity reversed A23187-stimulated mitochondrial ATP production. H(2)S improved mitochondrial ATP production in SMCs with hypoxia, which alone decreased ATP production. These results suggest that translocation of CSE to mitochondria on specific stress stimulations is a unique mechanism to promote H(2)S production inside mitochondria, which subsequently sustains mitochondrial ATP production under hypoxic conditions.     

硫化氢对大鼠实验性肝硬化门静脉压力的影响

目的应用内源性硫化氢（H2S）供体硫氢化钠（NaHS）探讨内源性H2S/胱硫醚-γ-裂解酶（CSE）体系对大鼠肝硬化门静脉压力的影响。方法将32只健康雌性SD大鼠随机分为4组：C组和C＋S组采用复合因素法复制肝硬化模型。模型制备52 d后,N＋S组和C＋S组大鼠腹腔注射NaHS 56μmol/（kg.d）,N组和C组腹腔注射同等剂量的生理盐水。1周后分别测定各组大鼠门静脉压力（PVP）及门静脉血浆中H2S含量;采用免疫组织化学方法检测大鼠肝门区门静脉平滑肌细胞中CSE蛋白表达。结果与N组和N＋S组相比,C组和C＋S组PVP均升高,H2S含量及CSE蛋白表达均降低;与C组相比,C＋S组PVP降低,H2S含量及CSE蛋白表达均升高。结论 NaHS作为H2S供体可能具有改善肝硬化大鼠门脉高压的作用,其机制可能与H2S含量及CSE蛋白表达升高有关。     

Targeting hydrogen sulfide as a promising therapeutic strategy for atherosclerosis

Physiological concentrations of nitric oxide (NO) and carbon monoxide (CO) have multiple protective effects in the cardiovascular system. Recent studies have implicated hydrogen sulfide (H₂S) as a new member of vasculoprotective gasotransmitter family, behaving similarly to NO and CO. H₂S has been demonstrated to inhibit multiple key aspects of atherosclerosis, including atherogenic modification of LDL, monocytes adhesion to the endothelial cells, macrophage-derived foam cell formation and inflammation, smooth muscle cell proliferation, neointimal hyperplasia, vascular calcification, and thrombogenesis. H₂S also decreases plasma homocysteine levels in experimental animal models. In the human body, H₂S production is predominantly catalyzed by cystathionine-β-synthase (CBS) and cystathionine γ-lyase (CSE). CSE is the primary H₂S-producing enzyme in the vasculature. Growing evidence suggests that atherosclerosis is associated with vascular CSE/H₂S deficiency and that H₂S supplementation by exogenous H₂S donors (such as NaHS and GYY4137) attenuates, and H₂S synthesis suppression by inhibitors (such as D, L-propargylglycine) aggravates the development of atherosclerotic plaques. However, it remains elusive whether CSE deficiency plays a causative role in atherosclerosis. A recent study (Circulation. 2013; 127: 2523–2534) demonstrates that decreased endogenous H₂S production by CSE genetic deletion accelerates atherosclerosis in athero-prone ApoE^−/− mice, pinpointing that endogenously produced H₂S by CSE activation may be of benefit in the prevention and treatment of atherosclerosis. This study will facilitate the development of H₂S-based pharmaceuticals with therapeutic applications in atherosclerosis-related cardiovascular diseases.     

Bile-acid-activated farnesoid X receptor regulates hydrogen sulfide production and hepatic microcirculation

AIM： To investigate whether the farnesoid X receptor（FXR） regulates expression of liver cystathionase （CSE）,a gene involved in hydrogen sulfide （H2S） generation.METHODS： The regulation of CSE expression inresponse to FXR ligands was evaluated in HepG2 cells and in wild-type and FXR null mice treated with 6-ethyl chenodeoxycholic acid （6E-CDCA）, asynthetic FXR ligand. The analysis demonstrated an FXR responsive element in the 5＇-flanking region ofthe human CSE gene. The function of this site was investigated by luciferase reporter assays, chromatin immunoprecipitation and electrophoretic mobility shiftassays. Livers obtained from rats treated with carbon tetrachloride alone, or in combination with 6-ethyl chenodeoxycholic acid, were studied for hydrogen sulphide generation and portal pressure measurement.RESULTS： Liver expression of CSE is regulated bybile acids by means of an FXR-mediated mechanism.Western blotting, qualitative and quantitative polymerasechain reaction, as well as immunohistochemical analysis,showed that expression of CSE in HepG2 cells andin mice is induced by treatment with an FXR ligand.Administration of 6E-CDCA to carbon tetrachloride treated rats protected against the down-regulation ofCSE expression, increased H2S generation, reduced portal pressure and attenuated the endothelial dysfunction of isolated and perfused cirrhotic rat livers.CONCLUSION： These results demonstrate thatCSE is an FXR-regulated gene and provide a newmolecular explanation for the pathophysiology of portal hypertension.     

Expert consensus on blood pressure management of diabetic patients in China (中国糖尿病患者血压管理专家共识)

This Expert Consensus proposed by the Chinese Society of Endocrinology (CSE) updates concepts on hypertension management in patients with diabetes. It focuses on clinical outcomes literature published within the past 5 years and currently in press, and incorporates these new observations into modifications of established guidelines. Complications and mortality in diabetic patients are increased when hypertension is present. The present update focuses on questions such as what to do when a diabetic patient has an elevated blood pressure level when therapy is initiated and whether combinations of agents should be used as soon as possible. Although the strategies and principles of treatment remain unchanged, approaches to specific patient‐related issues influencing cardiovascular outcomes in people with diabetes have changed. Finally, an updated integrated management of multiple cardiovascular risk factors is provided and is suggested as a starting point to achieve blood pressure goals. In addition to controlling blood pressure, the CSE suggests that individualized strategies are equally important and that attention should be paid to other factors, including safety (which is the most important), feasibility, and health economic evaluation.     

The hydrogen sulfide signaling system: changes during aging and the benefits of caloric restriction

Hydrogen sulfide gas (H₂S) is a putative signaling molecule that causes diverse effects in mammalian tissues including relaxation of blood vessels and regulation of perfusion in the liver, but the effects of aging on H₂S signaling are unknown. Aging has negative impacts on the cardiovascular system. However, the liver is more resilient with age. Caloric restriction (CR) attenuates affects of age in many tissues. We hypothesized that the H₂S signaling system is negatively affected by age in the vasculature but not in the liver, which is typically more resilient to age, and that a CR diet minimizes the age affect in the vasculature. To investigate this, we determined protein and mRNA expression of the H₂S-producing enzymes cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), H₂S production rates in the aorta and liver, and the contractile response of aortic rings to exogenous H₂S. Tissue was collected from Fisher 344 × Brown Norway rats from 8–38 months of age, which had been maintained on an ad libitum (AL) or CR diet. The results demonstrate that age and diet have differential effects on the H₂S signaling system in aorta and liver. The aorta showed a sizeable effect of both age and diet, whereas the liver only showed a sizeable effect of diet. Aortic rings showed increased contractile sensitivity to H₂S and increased protein expression of CSE and CBS with age, consistent with a decrease in H₂S concentration with age. CR appears to benefit CSE and CBS protein in both aorta and liver, potentially by reducing oxidative stress and ameliorating the negative effect of age on H₂S concentration. Therefore, CR may help maintain the H₂S signaling system during aging.     

The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis

The regulation of sinusoidal resistance is dependent on the contraction of hepatic stellate cells (HSC) around sinusoidal endothelial cell (SEC) through paracrine cross-talk of vasoconstrictor and vasodilator agents. Hydrogen sulfide (H2S), a recently discovered gas neurotransmitter, is a putative vasodilator whose role in hepatic vascular regulation and portal hypertension is unexplored. Four-week bile duct-ligated (BDL) rats with cirrhosis and control rats were treated daily with NaHS (56 micromol/kg) for 5 days. Isolated livers were perfused first with NaHS for 20 minutes and then with norepinephrine (NE) and the intrahepatic resistance studied. In normal rats and animals with cirrhosis, administration of NE resulted in a dose-dependent increase of portal pressure. This effect was attenuated by H2S treatment (P < .05). The H2S-induced relaxation of hepatic microcirculation was attenuated by glibenclamide, an adenosine triphosphate (ATP)-sensitive K+ channel inhibitor. L-Cysteine, a substrate of cystathionine-gamma-lyase (CSE), decreased vasoconstriction in normal rat livers (P < .05) but failed to do so in livers with cirrhosis. BDL resulted in a downregulation of CSE mRNA/protein levels and activity (P < .05). Our in vitro data demonstrate that CSE is expressed in hepatocytes, HSCs, but not in sinusoidal endothelial cells (SEC). HSC activation downregulates CSE mRNA expression, resulting in a defective production of H2S and abrogation of relaxation induced by L-cysteine. In conclusion, CSE-derived H2S is involved in the maintenance of portal venous pressure. The reduction of CSE expression in the liver with cirrhosis contributes to the development of increased intrahepatic resistance and portal hypertension.