非对称二甲基精氨酸—新的心血管疾病危险因子和药物防治靶点

多种心血管疾病的危险因素如高血脂症、高血压和糖尿病等能导致内皮依赖性血管舒张功能受损，血管内皮功能不全在心血管疾病的发生发展中起重要作用。一氧化氮(NO)是由一氧化氮合酶(NOS)催化L-精氨酸转化而来。精氨酸的同系物非对称二甲基精氨酸(ADMA)抑制NOS，阻止NO合成。内源性ADMA是由甲基化蛋白转移酶(PRMT)催化而成，被二甲基精氨酸二甲胺水解酶(DDAH)代谢失活，     

二甲基精氨酸二甲胺水解酶与心血管疾病

二甲基精氨酸二甲胺水解酶(DDAH)是一种胞浆蛋白酶,包括DDAH1和DDAH2两种亚型,能特异性水解内源性一氧化氮合酶(NOS)抑制物非对称二甲基精氨酸而上调NOS活性。DDAH与NOS活性之间的相互作用在调节NO生成和血管内皮功能中起重要作用。DDAH还参与血管新生与细胞分化的调节,其活性变化与动脉粥样硬化等多种心血管疾病的发生发展密切相关,可能是一个新的心血管疾病相关蛋白和药物防治靶点。     

糖尿病大鼠内源性ADMA升高与代谢控制的关系

目的　以链脲佐菌素诱导的糖尿病大鼠为实验模型 ,研究内源性一氧化氮合酶 (NOS)抑制物非对称性二甲基精氨酸 (ADMA)升高与糖尿病代谢控制的关系。方法　用高效液相色谱测定大鼠血清ADMA浓度 ;用离体胸主动脉环检测乙酰胆碱诱导的内皮依赖性舒张反应 ;并检测血糖、糖基化血清蛋白和血清脂质过氧化产物丙二醛 (MDA)浓度以反映代谢控制。结果　糖尿病大鼠血清ADMA浓度比正常组大鼠明显升高 ,并伴有离体血管内皮依赖性舒张反应的显著抑制 ;经胰岛素治疗 8wk后 ,不仅阻止内源性ADMA的升高 ,也明显改善血管的内皮依赖性舒张功能。此外 ,糖尿病大鼠血糖、糖基化血清蛋白和血清MDA水平也比正常组明显升高。用胰岛素改善代谢控制后 ,血糖、糖基化血清蛋白和血清MDA水平均恢复正常 ,血中ADMA浓度也显著降低。结论　糖尿病大鼠血中内源性NOS抑制物ADMA浓度升高与代谢控制密切相关 ;胰岛素逆转糖尿病大鼠内源性ADMA升高可能与纠正代谢紊乱和降低脂质过氧化有关     

非对称二甲基精氨酸水平与慢性阻塞性肺疾病患者疾病严重程度及肺动脉高压的关系

<正>一氧化氮(NO)是一种重要的内皮源性血管活性物质,主要由NO合酶(NOS)催化L-精氨酸转化而来,在维持血管结构和功能中起重要作用。体内存在内源性NOS抑制物非对称二甲基精氨酸(ADMA),能减少NO合成,进而损伤内皮功能。ADMA是NOS的内源性竞争抑制剂,在高胆固醇血症、冠状动脉疾病、外周动脉疾病、慢性心力衰竭、肺动脉高压(PAH)、卒中、肥厚性心肌病、糖尿病和慢性肾衰竭等多种疾     

不对称性二甲基精氨酸与脑梗死的相关性研究

内皮依赖性血管舒张反应功能障碍是动脉粥样硬化的特征性表现.一氧化氮(nitric oxide,NO)对维持内皮正常功能有重要作用.不对称性二甲基精氨酸(asymmetric dimethylarginine,ADMA)为一氧化氮合酶(nictric oxide synthase,NOS)抑制剂,它能竞争性抑制NOS活性,减少NO生成.在多种病理生理状况下ADMA水平显著升高,内皮细胞NOS活性降低,NO合成减少,导致血管内皮功能不全~([1]).本研究旨在通过检测脑梗死患者ADMA水平,探讨ADMA与脑梗死的相关性.     

内源性一氧化氮合酶抑制物与肺动脉高压研究进展

内源性一氧化氮合酶抑制物非对称二甲基精氨酸(ADMA)是近年来的研究热点,被认为是一种新的心血管疾病风险因子。其代谢主要经二甲基精氨酸二甲胺水解酶(DDAH)水解途径完成。ADMA/DDAH通路的失调可能引起内皮功能不全、肺血管重构等一系列病理改变并导致肺动脉高压形成。阐明ADMA在肺动脉发生发展中的作用对肺动脉高压防治具有重要意义。     

胰岛素抵抗与血管内皮细胞释放一氧化氮关系的研究进展

胰岛素抵抗(IR)是产生2型糖尿病、心血管疾病、高脂血症、高尿酸血症及代谢综合症的共同病理基础。IR产生机制尚未阐明,现已证实胰岛素抵抗会伴有内皮细胞功能紊乱,血管内皮受损是微血管和大血管病变的重要因素,并且内皮损伤伴有一氧化氮合酶(NOS)功能和一氧化氮(NO)释放紊乱。本综述将讨论内皮功能障碍和胰岛素抵抗的相关病理生理学机制,并确定检查内皮细胞中NO的释放量是否能确定患者患有胰岛素抵抗及伴有并发症,为临床检验提供依据。     

内皮型一氧化氮和酶及其抑制剂与2型糖尿病血管内皮功能

内皮型一氧化氮和酶(eNOS)是已知最重要的内源性血管舒张因子,其竞争性抑制剂非对称性二甲基精氨酸(ADMA),可抑制一氧化氮(NO)的合成,使NO/NOS通路发生障碍,NO合成减少.2型糖尿病(T2DM)内皮功能紊乱与氧化应激有关,内皮细胞的增殖及凋亡、缺氧/复氧损伤和NO介导的内皮舒张功能障碍均涉及eNOS和ADMA的变化.     

ADMA所致血管内皮功能障碍与心血管疾病

不对称二甲精氨酸(ADMA)为一氧化氮全酶(NOS)的内源性竞争性抑制剂,在动脉粥样硬化及具有动脉粥样硬化危险因素的患者的血浆中浓度明显升高,血浆ADMA水平与血管内皮功能障碍程度及动脉粥样硬化有关。已有研究表明,通过抑制一氧化氮(NO)的合成,ADMA影响血流及血管紧张度,促进动脉粥样硬化的形成,妨碍血管的生成。因此认为ADMA为心血管疾病的一种新型危险因子。本文对ADMA所致的血管内皮功能障碍及心血管疾病的关系作一综述,以供参考。1一氧化氮与血管内皮功能障碍一氧化氮(NO)是体内强有力的血管舒张剂,它通过剪切力作用于血管壁,…     

一氧化氮合酶基因治疗在心血管疾病中的应用

一氧化氮(NO)为内皮细胞舒血管因子(EDRF)，是心血管系统重要的调节因子，NO功能异常在许多心血管系统疾病的发病中起重要作用。催化NO合成的酶称为一氧化氮合酶(NOS)，用转基因方法转移重组NOS基因，重建内源性NO功能，是治疗心血管系统疾病的新策略，本文就重组NOS转基因的研究进行综述。     

内皮型一氧化氮合酶脱偶联的研究进展

血管内皮功能障碍(endothelial dysfunction)是多种心脑血管疾病的共同病理机制,其突出表现为内皮依赖性血管舒张功能障碍,主要由NO减少及氧自由基增加所致。最新研究发现,内皮型一氧化氮合酶脱偶联(eNOS uncoup ling)是导致NO水平下降和氧自由基水平升高的重要机制,是高血压、糖尿病、动脉粥样硬化等疾病中内皮功能障碍的重要原因。通过纠正eNOS脱偶联可有效改善内皮功能,有望为保护血管内皮功能提供有效途径。     

Elevated serum endogenous inhibitor of nitric oxide synthase and endothelial dysfunction in aged rats

1. The purpose of the present study was to determine the relationship between endothelial dysfunction and the endogenous inhibitor of nitric oxide synthase NG,NG'-asymmetric dimethylarginine (ADMA) in aged rats. 2. Studies were performed in male adult Sprague-Dawley rats (6 months old; n = 8) and in aged rats (20 months old; n = 8). Serum levels of ADMA and L-arginine were measured by high-performance liquid chromatography and responses of endothelium-intact aortic rings to acetylcholine (ACh) were tested. Nitric oxide synthase activity in kidney tissue and serum concentrations of nitrite, a stable end-product of nitric oxide, were assayed and serum contents of malondialdehyde, derived from lipid peroxidation and serum lipid and creatinine level were determined. 3. Serum levels of ADMA increased significantly in aged rats compared with adult rats (P < 0.01), whereas serum levels of L-arginine were similar in both groups (P = NS). Accordingly, the ratio of L-arginine/ADMA in old rats was lower than that in young rats (P < 0.01). Endothelium-dependent relaxation responses to ACh in aortic rings from aged rats were impaired and these impaired responses were improved by pre-incubation of aortic rings with L-arginine. 4. Nitric oxide synthase activity in the kidney, together with serum concentration of nitrite, was significantly decreased and serum contents of malondialdehyde, cholesterol and triglycerides were increased in old compared with young rats. However, the serum creatinine level was not significantly different between adult and aged rats. 5. Endogenous ADMA may be a contributor to age-related endothelial dysfunction and increases in endogenous ADMA may be linked to lipid peroxidation in aged rats.     

Korean Red Ginseng Water Extract Restores Impaired Endothelial Function by Inhibiting Arginase Activity in Aged Mice

Cardiovascular disease is the prime cause of morbidity and mortality and the population ages that may contribute to increase in the occurrence of cardiovascular disease. Arginase upregulation is associated with impaired endothelial function in aged vascular system and thus may contribute to cardiovascular disease. According to recent research, Korean Red Ginseng water extract (KRGE) may reduce cardiovascular disease risk by improving vascular system health. The purpose of this study was to examine mechanisms contributing to age-related vascular endothelial dysfunction and to determine whether KRGE improves these functions in aged mice. Young (10±3 weeks) and aged (55±5 weeks) male mice (C57BL/6J) were orally administered 0, 10, or 20 mg/mouse/day of KRGE for 4 weeks. Animals were sacrificed and the aortas were removed. Endothelial arginase activity, nitric oxide (NO) generation and reactive oxygen species (ROS) production, endothelial nitric oxide synthase (eNOS) coupling, vascular tension, and plasma peroxynitrite production were measured. KRGE attenuated arginase activity, restored nitric oxide (NO) generation, reduced ROS production, and enhanced eNOS coupling in aged mice. KRGE also improved vascular tension in aged vessels, as indicated by increased acetylcholine-induced vasorelaxation and improved phenylephrine-stimulated vasoconstriction. Furthermore, KRGE prevented plasma peroxynitrite formation in aged mice, indicating reduced lipid peroxidation. These results suggest KRGE exerts vasoprotective effects by inhibiting arginase activity and augmenting NO signaling and may be a useful treatment for age-dependent vascular diseases.     

Pharmacology in health foods: improvement of vascular endothelial function by French maritime pine bark extract (Flavangenol)

Flavangenol is the French maritime pine bark extract (PBE). It consists of a concentrate of pine bark constituents such as catechin, taxifolin, and proanthocyanidins. Recent studies have shown that PBE has a strong antioxidant effect and exerts ameliorative effects on cardiovascular, skin, cognitive, and menstrual disorders, as well as in the context of other diseases and disease processes such as diabetes and inflammation. We have also obtained evidence that Flavangenol suppresses nuclear factor-kappa B (NF-κB) activation and the subsequent various NF-κB-induced gene expressions such as those of adhesion molecules and endothelin-1 in cultured vascular endothelial cells and that the antihypertensive effect of Flavangenol on deoxycorticosterone acetate-salt hypertensive rats is attributable to both its antioxidative property-related protective effects against endothelial dysfunction and the endothelium-dependent vasorelaxant effect, which is mediated by endothelial nitric oxide synthase activation. Furthermore, Flavangenol showed a renoprotective effect on ischemia/reperfusion-induced acute kidney injury in rats. These findings suggest that Flavangenol supplementation may be a promising candidate for the improvement of endothelial dysfunction and the prophylactic treatment of vascular diseases.     

Lipoic acid supplementation and endothelial function

Endothelial dysfunction is caused by all the recognized cardiovascular risk factors and has been implicated in the complex processes leading to the initiation and progression of atherosclerosis. Short-term treatment with lipoic acid is shown in the current issue of the British Journal of Pharmacology to improve endothelial function of aortic rings of old rats. The age-related decrease in phosphorylation of nitric oxide synthase and Akt was improved by lipoic acid supplementation. The improved phosphorylation status may have been due to reduced activity of the phosphatase PPA2, associated with decreased levels of endothelial ceramide induced by lipoic acid. Neutral sphingomyelinase activity was also reduced by lipoic acid, which was due, at least in part, to increased glutathione levels in endothelial cells. The favourable antioxidant, anti-inflammatory, metabolic and endothelial effects of lipoic acid shown in rodents, in this and other recently published studies, warrant further assessment of its potential role for prevention and treatment of cardiovascular diseases.     

2,4,6-Trinitrotoluene inhibits endothelial nitric oxide synthase activity and elevates blood pressure in rats

2,4,6-Trinitrotoluene (TNT), which is widely used in explosives, is an important occupational and environmental pollutant. Human exposure to TNT has been reported to be associated with cardiovascular dysfunction, but the mechanism is not well understood. In this study, we examine the endothelial nitric oxide synthase (eNOS) activity and blood pressure value following TNT exposure. With a crude enzyme preparation, we found that TNT inhibited the enzyme activity of eNOS in a concentration-dependent manner (IC₅₀ value=49.4 μM). With an intraperitoneal administration of TNT (10 and 30 mg/kg) to rats, systolic blood pressure was significantly elevated 1 h after TNT exposure (1.2- and 1.3-fold of that of the control, respectively). Under the conditions, however, experiments with the inducible NOS inhibitor aminoguanidine revealed that an adaptive response against hypertension caused by TNT occurs. These results suggest that TNT is an environmental chemical that acts as an uncoupler of constitutive NOS isozymes, resulting in decreased nitric oxide formation associated with hypertension in rats.     

内皮一氧化氮合酶与代谢综合征的关系

代谢综合征是近年来国内外关注的热点,其主要特征为多种心血管代谢危险因素的聚集,其关键的病理生理机制涉及高血压、动脉粥样硬化、II型糖尿病、胰岛素抵抗等。研究表明内皮一氧化氮合酶参与高血压、动脉粥样硬化、II型糖尿病、胰岛素抵抗等病理过程。本文总结了一氧化氮合酶与代谢综合征之间的关系,以更好地为代谢综合征的治疗提供的思路。     

Arginase: a critical regulator of nitric oxide synthesis and vascular function

1. Arginase is the focal enzyme of the urea cycle hydrolysing L-arginine to urea and L-ornithine. Emerging studies have identified arginase in the vasculature and have implicated this enzyme in the regulation of nitric oxide (NO) synthesis and the development of vascular disease. 2. Arginase inhibits the production of NO via several potential mechanisms, including competition with NO synthase (NOS) for the substrate L-arginine, uncoupling of NOS resulting in the generation of the NO scavenger, superoxide and peroxynitrite, repression of the translation and stability of inducible NOS protein, inhibition of inducible NOS activity via the generation of urea and by sensitization of NOS to its endogenous inhibitor asymmetric dimethyl-L-arginine. 3. Upregulation of arginase inhibits endothelial NOS-mediated NO synthesis and may contribute to endothelial dysfunction in hypertension, ageing, ischaemia-reperfusion and diabetes. 4. Arginase also redirects the metabolism of L-arginine to L-ornithine and the formation of polyamines and L-proline, which are essential for smooth muscle cell growth and collagen synthesis. Therefore, the induction of arginase may also promote aberrant vessel wall remodelling and neointima formation. 5. Arginase represents a promising novel therapeutic target that may reverse endothelial and smooth muscle cell dysfunction and prevent vascular disease.     

Nitric Oxide Modulators: An Emerging Class of Medicinal Agents

Nitric oxide, a unique messenger in biological system, is ubiquitously present virtually in all tissues revealing its versatile nature of being involved in diverse physiological functions such as vascular tone, inhibition of platelet aggregation, cell adhesion, neurotransmission and enzyme and immune regulation. The tremendous advancements made in the past few decades in this area suggests that the nitric oxide modulation either by its exogenous release through nitric oxide donors or inhibition of its synthesis by nitric oxide synthase inhibitors in physiological milieu may provide newer clinical strategies for the treatment of some diseases. In this review, an attempt is made to document and understand the biological chemistry of different classes of nitric oxide modulators that would prove to be a fruitful area in the years to come.