SIRT1在糖尿病心肌病发病中的研究进展

糖尿病心肌病(DCM)是糖尿病患者的一种严重的心血管并发症。去乙酰化酶沉默信息调节因子2同源物1(SIRT1)作为机体重要的细胞内调控蛋白,在许多生物过程中发挥重要作用,包括减轻心肌细胞氧化应激、维持心肌线粒体Ca²⁺稳态、降低心肌内质网应激、改善心肌线粒体功能障碍以及抑制机体肾素-血管紧张素-醛固酮系统的活化等,可能是DCM的潜在治疗靶点,靶向SIRT1进行深入研究能够为DCM的临床治疗提供新的理论依据。就SIRT1在DCM的发病机制中的具体作用及治疗策略进行综述。     

血管内皮功能障碍与2型糖尿病及中医证型相关性研究进展

血管内皮功能是维持血管通透性、平衡凝血系统与纤溶系统及限制炎症活动的重要保障,而血管内皮功能障碍可导致一系列疾病发生发展,尤其是糖尿病(diabetes mellitus,DM)。血管内皮功能障碍被认为是DM血管病变的早期事件,血管内皮细胞受损贯穿DM及其并发症的发生发展过程。现对血管内皮功能与2型DM及中医证型相关性研究进展作一综述,旨在为临床提供一定参考。     

糖尿病血管内皮损伤的药物治疗

糖尿病血管并发症是糖尿病致死致残的主要原因,而血管内皮损伤是血管病变的基础。早期有效干预高糖性血管内皮损伤对于防治糖尿病血管并发症有积极意义。本文将对糖尿病血管内皮损伤的药物治疗最新进展进行综述。     

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。     

内皮祖细胞与妊娠糖尿病

妊娠糖尿病是糖尿病的特殊分型,其发病率呈升高趋势。妊娠糖尿病不仅增加了孕妇及新生儿的病死率,甚至对新生儿有远期的影响。我们的前期研究表明糖尿病一级亲属已经存在血管内皮功能障碍，血管内皮功能障碍是糖尿病血管并发症的始发因素，因此及时修复受损的血管内皮对预防及延缓糖尿病血管并发症的发生有重要的意义。     

胰岛素抵抗与血管内皮功能障碍

胰岛素抵抗和血管内皮功能障碍是代谢性疾病和心血管疾病的重要危险因素。胰岛素抵抗状态下存在内皮依赖性血管舒张功能障碍,内皮源性一氧化氮产生减少,形成内皮细胞胰岛素抵抗的新观点。糖毒性、脂质毒性及炎性状态是胰岛素抵抗与血管内皮功能障碍共同发病机制。改善胰岛素抵抗和血管内皮功能障碍对预防和治疗代谢性疾病和心血管疾病具有重要意义。     

维生素E对糖尿病患者血管内皮功能的影响

目的　观察抗氧化剂维生素 E对糖尿病患者血管内皮功能的影响。方法　采用随机、双盲法将入选糖尿病患者分为维生素 E( 10 0 m g/ d,连服 3个月 )治疗组及安慰剂组。应用高分辨率超声 ,检查了糖尿病患者治疗前后的肱动脉内皮依赖性及非内皮依赖性血管内径与血流变化。结果　与正常对照组比较 ,无论治疗组还是安慰剂组的糖尿病人 ,其血流介导的血管扩张性均明显降低 [( 6.7± 2 .1)比 ( 4 .4± 2 .1) ,P <0 .0 5 ;( 6.7±2 .1)比 ( 4 .3± 2 .4 ) ,P<0 .0 5 ],而硝酸甘油介导的血管内皮扩张性无显著改变 ;经维生素 E治疗 3个月后 ,糖尿病人内皮依赖性血管扩张功能较安慰剂组明显改善 [( 6.8± 3 .0 )比 ( 4 .4± 2 .1) ,P<0 .0 1]。结论　糖尿病患者存在血管内皮功能失调 ,而补充维生素 E可改善其血管内皮功能     

川芎嗪治疗糖尿病下肢血管病变疗效观察

目的 观察川芎嗪治疗糖尿病下肢血管病变的临床效果.方法 糖尿病下肢血管病变患者96例随机分为治疗组和对照组,治疗组给予川芎嗪,对照组给予丹参注射液20 ml,静脉滴注,1次/d,共2周,观察治疗前后症状缓解情况,检测足背动脉血流量、ABI和血液流变学变化.结果 治疗组治疗血流变、足背动脉血流量、下肢血管踝肱指数(ABI)较治疗前明显改善,与对照组比较差异具有统计学意义(P＜0.05).结论 川芎嗪具有明显改善糖尿病下肢血管病变的作用.     

罗格列酮对2型糖尿病患者胰岛β细胞功能及血管内皮功能的影响

目的 探讨罗格列酮对2型糖尿病患者胰岛β细胞功能及血管内皮功能的影响.方法 选择50例2型糖尿病患者,给予马来酸罗格列酮口服,起始剂量为4 mg、每日1次,4周后血糖改善不理想者增至8 mg、每日1次,疗程8周.观察治疗前后空腹血糖(FPG)、睡前血糖、餐后2 h血糖(2 h PG)、糖化血红蛋白(HbA1c)、空腹C肽(FCP)、餐后C肽(PCP)、血管性假血友病因子(vWF)、血栓调节蛋白(TM)水平的变化.结果 患者经罗格列酮治疗8周后,FPG,2 h PG、睡前血糖和HbA1c均较治疗前明显降低(P<0.05或P<0.01):血浆FCP和PCP均明显升高(P<0.01),血浆vWF和TM均明显下降(P<0.01).结论 罗格列酮治疗2型糖尿病在降低血糖的同时,能改善患者的胰岛β细胞功能和血管内皮功能,延缓糖尿病血管病变的发生发展.     

山茱萸环烯醚萜总苷对糖尿病大鼠胸主动脉血管内皮的保护作用

在发达国家，糖尿病大血管病变如糖尿病心脏病变导致50％的糖尿病人死亡，美国糖尿病心脏病居致死原因的第5位。糖尿病血管病变已严重地威胁着人类的健康,寻找能阻止或控制糖尿病血管病变发生、发展的有效药物已成为世界医药学研究的重点之一。现代研究认为，血管内皮损伤在糖尿病血管病变中是一早期的关键过程，故本文从形态学的角度观察其对糖尿病大鼠胸主动脉血管内皮的保护作用。     

Quercetin antagonism of Bay K 8644 effects on rat tail artery L-type Ca(2+) channels

Macroangiopathy is a major complication of diabetes mellitus in which dysfunction of vascular endothelium induced by excessive oxidative stress is an early and key determinant. As an endogenous antioxidant, taurine possesses endothelial protective effect in vitro. LOX-1 is an endothelial receptor for oxidized low-density lipoprotein (oxLDL) which might mediate endothelial dysfunction and subsequent atherogenesis in diabetes. We used streptozotocin-induced rats as models of type 1 diabetes to evaluate the protective effect of taurine against vascular endothelial dysfunction in type 1 diabetes and the possibly involved molecule mechanism. Eight male Wistar rats were used as normal control group. Sixteen diabetic rats induced by one single injection of streptozocin (60 mg/kg, i.p.) were randomly divided into two groups after the diabetes onset: diabetes mellitus group and taurine-treated diabetes group. 6 weeks afterward, endothelium-dependent vasodilation of isolated thoracic aorta, serum oxLDL and soluble intercellular adhesion molecule (sICAM-l) levels, LOX-1 and intercellular adhesion molecule (ICAM-1) expression on aortas were determined respectively. Streptozocin-induced diabetic rats were complicated with excessive oxidative stress and endothelial dysfunction: increased serum oxLDL and sICAM-1, inhibited endothelium-dependent vasodilator responses to acetylcholine (1 nM-0.1 microM). Simultaneously, LOX-1 and ICAM-1 expression were enhanced in aortas of diabetic rats; whereas blunted endothelium-dependent vasodilator responses to acetylcholine, increased serum oxLDL and sICAM-1 level as well as overexpression of LOX-1 and ICAM-1 were all attenuated significantly by taurine treatment. In conclusion, taurine improves vascular endothelial dysfunction induced by experimental type 1 diabetes and this effect might be associated with downregulation of LOX-1 and ICAM-1 expression on aortic vascular endothelium via its antioxidative property.     

Endothelial dysfunction in diabetes

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of different animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium-derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia-induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non-enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium-dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to differ according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.     

Role of the effect of inhibition of neutral endopeptidase on vascular and neural complications in streptozotocin-induced diabetic rats

We have previously shown that treating streptozotocin-induced diabetic rats, an animal model of type 1 diabetes, with Ilepatril (an inhibitor of neutral endopeptidase and angiotensin converting enzyme (ACE)) improves vascular and neural function. In this study we sought to determine the individual effect of inhibition of neutral endopeptidase and ACE on diabetes-induced vascular and neural dysfunction. After 4 weeks of untreated diabetes, rats were treated for 12 weeks with Ilepatril, Enalapril (ACE inhibitor) or Candoxatril (neutral endopeptidase inhibitor) followed by analysis of neural and vascular function. Diabetes caused slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber density in the hindpaw and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineural arterioles of the sciatic nerve and to atrial natriuretic peptide and calcitonin gene-related peptide in renal arteries. Inhibition of neutral endopeptidase or ACE improved neural function; however, dual inhibition of neutral endopeptidase and ACE with Ilepatril tended to have the greatest efficacy. Ilepatril and Candoxatril treatment of diabetic rats was more efficacious in improving vascular responsiveness in epineurial arterioles than treatment with Enalapril. Ilepatril, Enalapril or Candoxatril treatment of diabetic rats were all efficacious in renal arteries. These studies suggest that combination therapy may be the most effective approach for treatment of diabetic neural and vascular complications.     

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a relevant target for diabetic vasculopathy?

Mechanisms through which major risk factors accelerate diabetic angiopathy include low density lipoprotein (LDL) oxidation and advanced glycation end products (AGEs) formation. Lectin-like oxidized LDL receptor (LOX-1) is a newly identified vascular receptor for oxidized LDL (oxLDL) and AGEs. LOX-1 is up-regulated in vascular endothelium of diabetic animals and thus may be relevant to the development and progression of human diabetic vasculopathy. The mechanisms responsible for LOX-1 induction in diabetes remain unclear but appear to involve metabolic and inflammatory stimuli relevant to diabetes. Such factors may impact on LOX-1-mediated pro-atherogenic events, including endothelial dysfunction and plaque destabilization. Previous studies have shown that drugs commonly used in the treatment of type 2 diabetic patients, including statins and antidiabetic agents, inhibit endothelial LOX-1 expression. This review summarizes recent advances related to the role of LOX-1 in macrovascular diseases, its regulation by some derangements commonly found in diabetic patients and its modulation by vasculoprotective drugs.     

Insulin- and growth factor-resistance impairs vascular regeneration in diabetes mellitus

Diabetes and pre-diabetes are major contributors to cardiovascular mortality and morbidity. Insulin resistance is a key pathophysiological determinant of the metabolic and vascular abnormalities noted in these disorders. Ineffective vascular repair is likely to be an important contributor to the development of endothelial dysfunction, and subsequently atherosclerosis, in patients with diabetes. Beyond the systemic effects of the insulin resistant phenotype, including factors such as dysglycaemia and inflammation, cellular insulin resistance is emerging as an important factor in diabetic vascular disease. Disordered signal transduction via the PI3-kinase/Akt and MAP-kinase cascades is a hallmark of cellular insulin resistance, and such changes have been linked with both endothelial dysfunction and impaired angiogenesis. In this review we highlight the importance of insulin resistance to vascular repair and regeneration, discuss important cross-talk between the intracellular signalling of insulin and key pro-angiogenic molecules, and link these concepts to common patterns of vascular disease.     

Ameliorative effect of berberine on endothelial dysfunction in diabetic rats induced by high-fat diet and streptozotocin

Berberine can improve insulin resistance, lower blood glucose, and regulate lipid metabolism disorders which cause endothelial dysfunction, leading to vascular complications of type 2 diabetes mellitus. The aim of the present study was to investigate the effects of berberine on endothelial dysfunction of aortas in type 2 diabetes mellitus rats and its mechanism. Wistar rats were randomly divided into four groups: diabetic rats, control rats, diabetic rats treated with berberine (100 mg/kg), and control rats treated with berberine. The serum fasting blood glucose, insulin, total cholesterol, triglyceride and nitric oxide (NO) levels were tested. Acetylcholine-induced endothelium-dependent relaxation and sodium nitroprusside induced endothelium-independent relaxation were measured in aortas for estimating endothelial function. The expression of endothelial nitric oxide synthase (eNOS) mRNA was measured by RT-PCR, and the protein expressions of eNOS and NADPH oxidase (NOX4) were analyzed by western blot. The results showed that berberine significantly decreased fasting blood glucose, and triglyceride levels in diabetic rats. Berberine also improved endothelium-dependent vasorelaxation impaired in aorta. The expressions of eNOS mRNA and protein were significantly increased, while NOX4 protein expression was decreased in aortas from diabetic rats with berberine treatment. Moreover, serum NO levels were elevated after berberine treatment. In conclusion, berberine restores diabetic endothelial dysfunction through enhanced NO bioavailability by up-regulating eNOS expression and down-regulating expression of NADPH oxidase.     

L-Arginine: a novel therapy for coronary artery disease?

Coronary artery disease (CAD) is a significant cause of morbidity and mortality today. The treatment of CAD is improving, but its prevalence is increasing: both primary and secondary prevention measures are of vital importance. Atherosclerosis starts at an early age; it is initiated at the vascular endothelium level, a single layer entity that modulates vascular function. Modulation of vascular function is carried out through the L-arginine/nitric oxide (NO) pathway. Normal endothelial function requires an intact L-arginine/NO pathway and endothelium. Endothelial dysfunction may be a precursor to overt CAD. CAD risk factors have been shown to influence endothelial function, and the treatment of these risk factors can restore endothelial function. L-Arginine is a safe, novel, semiessential amino acid that increases NO production, thereby improving endothelial function. L-Arginine/NO has numerous beneficial neurohormonal modulating properties. Numerous animal model and human studies have been carried out to assess L-arginine in CAD and other related disorders such as congestive heart failure (CHF), peripheral vascular disease (PVD) and acute myocardial infarction (AMI). Prospective clinical trials are required to assess the promising role of L-arginine in CAD and related disorders     

皂苷类成分对血管内皮细胞功能的调节作用研究进展

血管内皮细胞在维持血管生理稳态中发挥了重要的作用,其功能障碍是动脉粥样硬化、冠心病、脑卒中、肿瘤等多种重大疾病发生发展的病理基础,调节血管内皮细胞功能是防治上述疾病的主要途径之一。大量研究表明,皂苷类成分可通过改善血管内皮功能达到治疗疾病的目的。综述了近年来报道的皂苷类成分调节血管内皮功能的研究进展,旨在为皂苷类成分作用机制的阐明和相关重大疾病的防治提供一定参考。     

Molecular targets of diabetic vascular complications and potential new drugs

In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered to be the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite, that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolsis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. These new findings may explain why classical antioxidants, like vitamin E, that work scavenging already formed toxic oxidation products, have failed to show beneficial effects on diabetic complications, and suggest new and attractive "causal" antioxidant therapy. New, low molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, that work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34 and FP15, which block protein kinase beta isoform, poly(ADP-ribose) polymerase and peroxynitrite, respectively. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolidinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. This preventive activity against oxidative stress generation can justify a large utilization and association of this compounds for preventing complications in diabetic patients where antioxidant defences have been shown to be defective.