VEGF和HGF与糖尿病血管合并症的相关性研究

目的:探讨血管内皮细胞生长因子(VEGF)和肝细胞生长因子(HGF)与糖尿病血管合并症的关系。方法:用ELISA法测定126例2型糖尿病和30例正常人(对照组)血清VEGF和HGF浓度,观察其与血糖、血脂、血压、肝肾功能以及糖尿病血管合并症的关系。结果:糖尿病组有血管合并症者血清VEGF高于无血管合并症者及对照组(P<0.05),而后2组差异无统计学意义;甘油三酯、低密度脂蛋白、缺血性心脏病、闭塞性动脉硬化和视网膜病变是影响血清VEGF水平的危险因素。糖尿病组血清HGF低于对照组,糖尿病微血管合并症组血清HGF低于大血管合并症组和无血管合并症组(P<0.05);空腹血糖、糖尿病神经病变、肾病和周围神经病变是影响HGF水平的危险因素。VEGF与HGF未见直线相关性。结论:VEGF与血管合并症密切相关,缺氧会代偿性诱导体内合成分泌大量VEGF,而与血糖无关;高血糖抑制HGF的合成,而与血管合并症间未见明显相关。     

Protection against myocardial ischemia/reperfusion injury by short-term diabetes: enhancement of VEGF formation, capillary density, and activation of cell survival signaling

The aims of this study were to determine effects of diabetes duration on myocardial ischemia/reperfusion (I/R) injury and test whether time-dependent differences in sensitivity of the streptozotocin diabetic rat heart to I/R are related to differences in vascular density, levels of vascular endothelial growth factor (VEGF) or endothelial nitric oxide synthase (eNOS) expression, NO formation, activation of Akt, and/or oxidative stress. After 2 or 6 weeks of streptozotocin-induced diabetes, I/R injury was induced by occlusion (30 min) and reperfusion of the left descending coronary artery. After 2 weeks of diabetes, infarct size and cleavage of caspase-3, a proapoptosis signal, were decreased as compared with normoglycemic controls or rats that had been diabetic for 6 weeks, whereas capillary density and levels of VEGF and eNOS protein and cardiac NO_x levels were all increased. Phosphorylation of Akt, a prosurvival signal, was also significantly increased after 2 weeks of diabetes. Cardiac lipid peroxidation was comparable to controls after 2 weeks of diabetes, whereas levels of nitrotyrosine, a peroxynitrite biomarker, were reduced. After 6 weeks of diabetes, lipid peroxidation was increased and levels of VEGF and plasma NO were reduced as compared with controls or rats diabetic for 2 weeks. Our results indicate endogenous cardioprotective mechanisms become transiently activated in this early stage of diabetes and that this may protect the heart from I/R injury through enhancement of VEGF and eNOS expression, NO formation, activation of cell survival signals, and decreased oxidative stress.Dr. Ma was on leave from the Sports Hospital, Sports Technical Institute of Guangdong, Guangzhou, China 510100. Dr. Al-Shabrawey is on leave from the Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt.     

Endothelin levels in experimental diabetes combined with cardiac hypertrophy

Diabetes mellitus is associated with endothelial and cardiac dysfunction, and endothelin has been suggested to alter cardiac function by being a positive inotropic agent, modulating the Frank-Starling response, contracting the coronary arteries and inducing tissue proliferation. We investigated endothelin levels in diabetic and in healthy dogs, 1 and 3 days after placing arteriovenous shunts (8 weeks after diabetes induction) in the femoral regions. Right and left ventricular weight/body weight ratios and Nterminal- atrial natriuretic peptide were increased in shunted animals (P < 0.05). Plasma endothelin levels were comparable in healthy and diabetic dogs. Shunted circulation did not change systemic endothelin levels in healthy dogs but reduced endothelin levels in diabetic dogs. The functional significance of altered endothelin responses to acute hemodynamic burden in experimental diabetes needs further investigation.     

Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress

Retinal neovascularization and macular edema are central features of diabetic retinopathy, a major cause of blindness in working age adults. The currently established treatment for diabetic retinopathy targets the vascular pathology by laser photocoagulation. This approach is associated with significant adverse effects due the destruction of neural tissue and is not always effective. Characterization of the molecular and cellular processes involved in vascular growth and hyperpermeability has led to the recognition that the angiogenic growth factor and vascular permeability factor VEGF (vascular endothelial growth factor) play a pivotal role in the retinal microvascular complications of diabetes. Thus, VEGF represents an important target for therapeutic intervention in diabetic retinopathy. Agents that directly inhibit the actions of VEGF and its receptors show considerable promise, but have not proven to be completely effective in blocking pathological angiogenesis. Therefore, a better understanding of the molecular events that control VEGF expression and mediate its downstream actions is important to define more precise therapeutic targets for intervention in diabetic retinopathy. This review highlights the current understanding of the process by which VEGF gene expression is regulated and how VEGF's biological effects are altered during diabetes. In particular, cellular and molecular alterations seen in diabetic models are considered in the context of high glucose-mediated oxidative stress effects on VEGF expression and action. Potential therapeutic strategies for preventing VEGF overexpression or blocking its pathological actions in the diabetic retina are considered.     

2型糖尿病肾病患者血管内皮生长因子检测及意义

目的 探讨糖尿病肾病（DN）患者血管内皮生长因子（VEGF）水平变化.方法 用酶联免疫法测定60例糖尿病肾病组（DN组）、65例糖尿病非肾病组（NDN组）患者和40例正常对照组血浆中血VEGF、糖化血红蛋白（HbA1c）及尿微量白蛋白（UmALB）的水平.结果 DN组和NDN组患者VEGF、HbA1c及UmALB水平均明显高于正常对照组（P＜0.01）;DN组VEGF、HbA1c及UmALB明显高于NDN组（P＜0.01）;两组糖尿病患者血浆VEGF与HbA1c、UmALB水平呈显著正相关（P＜0.05）.结论 糖尿病患者血浆VEGF明显升高,可能参与DN的发生和发展过程.     

Different role of endothelin ETA and ETB receptors and endothelial modulators in diabetes-induced hyperreactivity of the rabbit carotid artery to endothelin-1

The influence of diabetes on regulatory mechanisms and specific receptors implicated in the contractile response of isolated rabbit carotid arteries to endothelin-1 was examined. Endothelin-1 induced a concentration-dependent contraction that was greater in arteries from diabetic rabbits than in arteries from control rabbits. Endothelium removal or N(G)-nitro-L-arginine enhanced contractions in response to endothelin-1 only in control arteries, without modifying the endothelin-1 response in diabetic arteries. Indomethacin, furegrelate (thromboxane A(2) inhibitor), or cyclo-(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123; endothelin ET(A) receptor antagonist) inhibited the contractions in response to endothelin-1, the inhibition being greater in diabetic arteries than in control arteries. 2,6-Dimethylpiperidinecarbonyl-gamma-methyl-Leu-N(in)-(methoxycarbonyl)-D-Trp-D-Nle (BQ-788; endothelin ET(B) receptor antagonist) enhanced the contraction elicited by endothelin-1 in control arteries and displaced to the right the contractile curve for endothelin-1 in diabetic arteries. In summary, diabetes induces hyperreactivity of the rabbit carotid artery to endothelin-1 by a mechanism that at least includes: (1) enhanced activity of muscular endothelin ET(A) receptors; (2) impairment of endothelin ET(B) receptor-mediated nitric oxide (NO) release; and (3) enhancement of the production of thromboxane A(2).     

Vascular endothelin in hypertension

Endothelins are powerful vasoconstrictor peptides that also play numerous other functions in many different organs. Endothelin-1 (ET-1) is the most abundant and important of this family of peptides in blood vessels. Production of ET-1 is increased in the endothelium and the kidney in salt-dependent models of hypertension (e.g.: DOCA-salt rats and Dahl salt-sensitive rats, in salt-loaded SHR-SP, in angiotensin II-infused and in diabetic rats). ET-1 elicits an inflammatory response by increasing oxidant stress in the vascular wall, which induces vascular remodeling and endothelial dysfunction found in the hypertensive models that exhibit an endothelin-mediated component. Endothelin receptor antagonism reduces blood pressure and vascular hypertrophic remodeling present in these hypertensive models. Patients with stage 2 hypertension have enhanced vascular expression of ET-1. Endothelin receptor antagonists lower blood pressure in hypertensive patients. They could become therapeutic agents for prevention of target organ damage in hypertension and in type 2 diabetes, chronic renal failure and congestive heart failure. Side effects of endothelin receptor blockers have prevented up to the present their development for these indications. New endothelin antagonists devoid of these side effects, or alternatively inhibitors of the endothelin converting enzymes that generate ET-1 may in the future become available to block the endothelin system. However, to date endothelin antagonists have been approved only for the treatment of primary pulmonary hypertension, a rapidly fatal condition in which the endothelin system plays an important role and endothelin antagonists exert favorable effects.     

Contribution of endothelin receptors and cyclooxygenase-derivatives to the altered response of the rabbit renal artery to endothelin-1 in diabetes

The influence of diabetes on regulatory mechanisms and specific receptors implicated in the response of isolated rabbit renal artery to endothelin-1 was examined. Endothelin-1 induced a concentration-dependent contraction that was less potent in arteries from diabetic rabbits than in arteries from control rabbits. Endothelium removal or N(G)-nitro-L-arginine (L-NOARG) enhanced contractions to endothelin-1 either in control and diabetic arteries. Indomethacin inhibited endothelin-1-induced response in control arteries, but enhanced it in diabetic arteries. In contrast to that observed in rubbed and in L-NOARG treated arteries, in the presence of indomethacin the contractile action of endothelin-1 was higher in diabetic arteries than in control arteries. Nimesulide enhanced endothelin-1 contractions both in control and diabetic arteries. Cyclo-(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123, endothelin ET(A) receptor antagonist), attenuated endothelin-1 vasoconstriction in control rabbits, while vasoconstriction resulted increased in diabetic rabbits. 2,6-Dimethylpiperidinecarbonyl-gamma-Methyl-Leu-N(in)-(Methoxycarbonyl)-D-Trp-D-Nle (BQ-788, endothelin ET(B) receptor antagonist), enhanced the contractile response in control rabbit arteries without modifying this response in diabetic rabbits. In summary, diabetes decreases the sensitivity of the rabbit renal artery to endothelin-1 by decreasing the ratio between vasoconstrictor and vasodilator prostanoids released after activation of endothelin ET(A) receptors.     

糖尿病肾病患者血清血管内皮生长因子影响因素分析

目的　分析影响 2型糖尿病肾病 (DN)患者血清血管内皮生长因子 (VEGF)水平的因素。方法　采用双抗夹心ELISA法检测 12 2例糖尿病患者血清VEGF水平并与 4 0例健康体检者的血清VEGF水平作对比分析。使用SPSS10 0统计软件包对糖化血红蛋白 (GHbAlc)、血糖、尿白蛋白 (UALB)和肌酐 (Cr)等影响因素进行统计比较分析。结果　非糖尿病肾病 (NDN)组和糖尿病肾病组患者血清VEGF水平明显高于正常对照组(P =0 0 33;P =0 0 0 0 ;P =0 0 0 0 ) ;DN组患者血清VEGF水平明显高于NDN组 (P =0 0 2 0 ;P =0 0 0 0 ) ;糖尿病肾病患者血清VEGF水平受糖化血红蛋白、尿白蛋白等因素影响 (P =0 0 0 0 ;P =0 0 0 0 )。结论　糖尿病患者血清VEGF水平明显升高 ,糖尿病肾病患者血清VEGF水平受糖化血红蛋白、尿白蛋白等因素的影响 ,且随尿白蛋白的增加而增高 ,高水平的血清VEGF有可能参与糖尿病肾病的发生、发展过程 ,并在一定程度上反映病情的严重程度。     

Anti-angiogenesis drugs in diabetic retinopathy

The vascular endothelial growth factor (VEGF) plays a key role in the development of proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME), resulting in a significant visual loss among patients with diabetes mellitus. Systemic VEGF-A and the interplay between membrane-bound VEGF receptors and VEGF-R1 (soluble form) are key to angiogenesis and vasculogenesis. Furthermore, patients with diabetes have a higher risk of hypertension and proteinuria, two surrogate markers of systemic VEGF inhibition. Pegaptanib, ranibizumab, bevacizumab and roboxistaurin are the currently available anti-VEGF agents. Agents with activity occurring later down the angiogenic pathway and those drugs with potential to synergize with anti-VEGF-A technologies are being developed. In recent years, inhibition of ocular VEGF has emerged as a promising treatment modality for diabetes and is currently undergoing evaluation in clinical trials. A potential role for these anti-VEGF agents in the prevention of PDR and DME are also emerging.     

Renal protective effect of YM598, a selective endothelin type A receptor antagonist

We have investigated the protective effect of YM598, a selective endothelin type A receptor antagonist, against an endothelin-1-induced proliferation of rat mesangial cells and renal function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type II diabetes. YM598, but not K-8794, a selective endothelin type B receptor antagonist, inhibited the endothelin-1-induced proliferation of cultured mesangial cells derived from intact Wistar rats in a concentration-dependent manner. YM598 (0.1 or 1 mg/kg), enalapril (5 mg/kg), an angiotensin- converting enzyme inhibitor, or vehicle was administered once daily by gastric gavage to 22-week-old male OLETF rats for 32 weeks. YM598 blunted the development of albuminuria in a dose-dependent manner. A higher dose of YM598 reduced albuminuria comparable with enalapril. Urinary endothelin-1 excretion was greater in the diabetic rats than in the control rats, and was not substantially influenced by the agents. Enalapril, but not YM598, mildly lowered the blood pressure in the diabetic rats, indicating that blood pressure reduction is not involved in the major mechanism of the renoprotective effect of YM598 in OLETF rats. These data suggest that endothelin is involved in the progression of diabetic nephropathy in OLETF rats, and an endothelin type A antagonist is promising for the treatment of diabetic nephropathy.     

血管内皮生长因子、Klotho蛋白与2型糖尿病肾病的研究进展

糖尿病肾病是糖尿病的严重并发症之一。近年来研究表明血管内皮生长因子（VEGF）的异常表达与糖尿病肾病的发生发展密切有关,而klotho蛋白作为一种新发现的基因,也参与其过程,且二者相互作用可以加速糖尿病的发展。深入认识VEGF、klotho蛋白将为预防和治疗糖尿病肾病提供新的思路。     

Renal protective effect of YM598, a selective endothelin ET(A) receptor antagonist,against diabetic nephropathy in OLETF rats

We have investigated the effect of potassium (E)-N-[6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidin-4-yl]-2-phenylenthenesulfonamidate (YM598), a selective endothelin ET(A) receptor antagonist, on renal function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type II diabetes. YM598 (0.1 or 1 mg kg(-1)), enalapril (5 mg kg(-1)), an angiotensin-converting enzyme inhibitor, or vehicle was administered once daily by gastric gavage to 22-week-old male Otsuka Long-Evans Tokushima Fatty rats for 32 weeks. Enalapril but not YM598 mildly lowered blood pressure in the diabetic rats. YM598 blunted the development of albuminuria in a dose-dependent manner. High dose of YM598 reduced albuminuria comparable to enalapril. Urinary endothelin-1 excretion was greater in the diabetic than in the control rats, and was not substantially influenced by the agents. These data suggest that endothelin is involved in the progression of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats, and an endothelin ET(A) receptor antagonist may be useful for the treatment of diabetic nephropathy.     

Angiotensin-converting enzyme activity and angiomodulatory effects of sera in patients with diabetic retinopathy

Aberrant neovascularization plays a crucial role in ocular complications in diabetic patients. Sera from these patients contain high levels of angiostimulatory factors, the most important of which is vascular endothelial growth factor (VEGF). Many authors have described elevation of angiotensin-converting enzyme (ACE) activity in the sera of diabetic patients. It is important to determine the possible relationship between these two phenomena. We studied ACE serum activity and VEGF concentrations in patients with type 1 and type 2 diabetes and retinopathy We also investigated the effect of their sera on cutaneous angiogenesis induced in mice by grafting healthy human mononuclear blood leukocytes. We found a negative correlation between the angiostimulatory effect and ACE level in the sera of patients with type 1 diabetes and no correlation between these two parameters in patients with type 2 diabetes. VEGF concentrations were lower and ACE activity was significantly higher in the sera of patients with type 1 diabetes than in the sera of those with type 2 diabetes.     

Involvement of ET-1 in diabetic cardiomyopathy, vascular abnormality and nepropathy which are regressed by a novel endothelin receptor antagonist Dajisentan.

AIM: An impaired endothelium contributes to diabetic cardiomyopathy (CMP), vascular pathy (VSP) and nephropathy (NPP) in diabetes. It is hypothesized that these disorders which are the consequence to damaged endothelium could be recovered by Dajisentan, a novel dual endothelin receptor antagonist, developed by us as an investigated new drug. METHODS: Rat diabetes model was developed by ip streptozotocin and the     

Upregulation of vascular ET(B) receptor gene expression after chronic ET(A) receptor blockade in prediabetic NOD mice

In the aorta of prediabetic non-obese diabetic mice, a model of human type 1 diabetes, we investigated gene expression of the endothelin receptors and contractility to big endothelin-1 and endothelin-1 at the ages of 10 and 16 weeks. A subgroup of 10- week-old animals was treated with the endothelin ETA receptor antagonist LU461314 (30 mg/kg per day for 6 weeks). Blood glucose levels were normal in all animals. Real-time polymerase chain reaction analysis revealed that vascular ETB receptor expression was higher in 10-week-old non-obese diabetic (NOD) mice compared with controls. In 16-week-old NOD mice, but not in control mice, ETB receptor mRNA was twofold lower (P < 0.05 vs 10-week-old NOD mice). In all groups ETA receptor expression was unaffected by age or treatment. Contractions to big endothelin-1 and endothelin-1 were lower in 10-week-old NOD mice compared with controls. Treatment with LU461314 increased ETB receptor expression in 16-week-old NOD mice, but had no effect on vascular contractility. These data indicate that dysregulation of ETB receptor expression and a decreased contractile response to big endothelin-1 and endothelin-1 are present in the prediabetic state of a model of human type 1 diabetes. These alterations occur independent of glucose levels. Furthermore, ETA receptor blockade is effective in increasing ETB receptor gene expression, suggesting a potential role for endothelin ETA antagonists in the treatment of type 1 diabetes.     

辛伐他汀治疗糖尿病合并冠心病的疗效观察

目的 观察辛伐他汀治疗糖尿病合并冠心病的临床疗效.方法 选择47例糖尿病合并冠心病患者,均给予口服辛伐他汀20mg/次,1天1次,连续治疗12周,治疗前后均检测患者血糖、血脂、血浆一氧化氮(NO)与内皮索(ET)水平以及血清定粉样蛋白A(A-SAA),并测定血管内皮细胞的功能.结果 47例患者经过12周的治疗,血脂和肱...     

Serum vascular endothelial growth factor and diabetic nephropathy progression

To determine the serum levels of vascular endothelial growth factor (VEGF) at different stages of diabetic nephropathy. Study subjects were divided into three groups: subjects in group 1 were microalbuminuric diabetic (n = 33), in group 2 subjects were normoalbuminuric diabetic group (n = 32), and group 3 was formed from nondiabetic healthy control subjects (n = 18). VEGF, microalbuminuria, HbA1c, creatinine, triglycerides, total cholesterol, fasting serum glucose, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were measured. Serum VEGF concentrations were significantly higher in the diabetic groups than in the control group even at the normoalbuminuric stage. Serum VEGF levels were higher in the microalbuminuria group than in the normoalbuminuria group. Serum VEGF levels increased with diabetic nephropathy stage. In the diabetic group, serum VEGF appeared to be positively correlated with fasting plasma glucose, HbA1c, LDL, creatinin and microalbuminuria. Serum VEGF was found to be negatively correlated with serum HDL. We have shown that serum levels of VEGF represents an early marker of generalized vascular dysfunction, and this peptide contributes to endothelial damage in diabetes. Elevated serum VEGF levels in the normoalbuminuric stage could indicate that generalized vascular dysfunction is present even at this stage.     

2型糖尿病肾病患者血清VEGF、IL-6及TNF-α水平的检测与意义

目的：探讨2型糖尿病（T2DM）患者血管内皮生长因子（VEGF）、白细胞介素-6（IL-6）和肿瘤坏死因子（TNF-α）水平的变化及其临床意义。方法应用放射免疫法对40例2型糖尿病肾病患者、36例2型糖尿病非肾病患者及38例健康人（健康对照组）进行血清VEGF、IL-6及TNF-α水平的检测。结果2型糖尿病肾病组血清VEGF、IL-6及TNF-α水平显著高于健康对照组（P＜0.01）及2型糖尿病非肾病组（P＜0.01）。结论 VEGF、IL-6及TNF-α是2型糖尿病肾病发生的重要炎症反应介质,提示高水平的VEGF、IL-6及TNF-α可能在T2DM及其肾病并发症的发生、发展过程中起到一定作用,检测其水平变化可作为2型糖尿病肾病临床诊断的参考依据。