血管内皮生长因子预防血管成形术后再狭窄的机制研究

目的:探讨血管内皮生长因子(VEGF)预防血管成形术后再狭窄的机制.方法:用高脂饲养建立实验性动脉粥样硬化家兔模型,将VEGF作用于正常健康兔和动脉粥样硬化家兔主动脉血管内皮细胞(VEC).采用亚硝酸还原法测一氧化氮(NO),放免法测内皮素(ET)、6-酮-前列腺素1α( 6-keto-PGF1α),采用发色底物显色法测定血浆纤溶酶原激活物(t-PA)和纤溶酶原激活物抑制物-1(PAI-1)活性.并用WST-1比色法观察VEGF对上述VEC增殖的影响.结果:与空白对照组(VEGF 0 μg/L)比较, 10 μg/L、20 μg/L VEGF处理组NO、6-keto-PGF1α、PAI均明显增加,而ET、t-PA、t-PA/PAI均明显降低,并呈剂量依赖性.与正常健康兔VEC(正常VEC)比较,动脉粥样硬化家兔VEC(异常VEC)分泌ET、PAI、t-PA均明显增加,而NO、6-keto-PGF1α、t-PA/PAI均明显降低.结论:动脉粥样硬化家兔伴有内皮功能异常,而VEGF能促进正常和异常VEC的增殖并分泌NO、PGI2、PAI,而抑制ET、t-PA的分泌,使t-PA/PAI降低.     

Inhibition of neointimal formation after balloon injury by cilostazol, accompanied by improvement of endothelial dysfunction and induction of hepatocyte growth factor in rat diabetes model

Aims/hypothesis: Cilostazol, a well-known phosphodiesterase type 3 (PDE3) inhibitor for the treatment of peripheral arterial disease, has vasodilator properties and an anti-proliferative action on the growth of vascular smooth muscle cells. In this study, we tested whether cilostazol inhibits neointimal formation and improves endothelial dysfunction after balloon injury in non-diabetic and diabetic rats. Methods: Cilostazol or vehicle was administered to non-diabetic and streptozotocin-induced diabetic rats from 7 days before to 14 days after balloon injury of the carotid artery. We focused on the expression of hepatocyte growth factor to explore how cilostazol improved endothelial dysfunction. Also, we studied the effects of cilostazol on hepatocyte growth factor production in in vitro experiments. Results: At 14 days after injury, the ratio of neointimal to medial area was decreased in rats treated with cilostazol in non-diabetic and diabetic animals. The impaired response to acetylcholine in balloon injured vessels was improved by cilostazol in non-diabetic and diabetic rats (p < 0.05). Vascular hepatocyte growth factor concentration was decreased in injured vessels of non-diabetic rats compared to uninjured vessels. Moreover, hepatocyte growth factor was further decreased in injured vessels of diabetic rats as compared to those of non-diabetic rats (p < 0.05). Of note, administration of cilostazol attenuated the decrease in hepatocyte growth factor concentration in injured vessels of both non-diabetic and diabetic rats (p < 0.01). Increase in vascular hepatocyte growth factor by cilostazol was confirmed by in vitro experiments showing that cilostazol increased hepatocyte growth factor concentration in cultured human vascular smooth muscle cells, accompanied by cAMP accumulation. Conclusion/interpretation: Our study shows that the increase in vascular hepatocyte growth factor by cilostazol could improve abnormal growth of vascular smooth muscle cells and endothelial dysfunction through rapid regeneration of endothelial cells. [Diabetologia (2001) 44: 1034–1042] Received: 2 March 2001 and in revised form: 23 April 2001     

RA系统和前列腺素在实验性糖尿病早期肾脏高功能状态中的作用

观察了实验性糖尿病大鼠早期肾功能、ＲＡ系统和前列腺素的改变，发现在糖尿病形成８天后尿蛋白排泄量明显增加，用Ｃａｐｔｏｐｒｉｌ后与正常对照组无差异。ＧＦＲ和ＲＰＦ明显增加，用Ｃａｐｔｏｐｒｉｌ或消炎痛后与正常组无差异。上述结果提示ＲＡ系统和前列腺素均参与了糖尿病早期肾脏高功能状态的形成。     

Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases

Abstract

Angiogenesis plays an important role in the progression of rheumatic disease. We measured the levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in sera from patients with rheumatic diseases and investigated whether these angiogenic factors would be useful in the evaluation of rheumatic diseases. Serum VEGF and HGF levels were determined using ELISA in 128 patients with rheumatic diseases and in 11 healthy controls. Serum VEGF and HGF levels were significantly higher in patients with rheumatic diseases compared to healthy controls [VEGF, 312 ± 20?pg/ml versus 61 ± 8?pg/ml (mean ± SE), P < 0.001; HGF, 935 ± 36?pg/ml versus 413 ± 49?pg/ml, P < 0.01]. Serum VEGF and HGF levels were significantly elevated in patients with adult Still's disease (VEGF, 1021 ± 258?pg/ml; HGF, 1500 ± 295?pg/ml) and were relatively increased in patients with active rheumatoid arthritis (RA) (VEGF, 359 ± 94?pg/ml) and systemic sclerosis (SSc) (VEGF, 356 ± 43?pg/ml; HGF, 1294 ± 224?pg/ml). HGF levels correlated with the clinical course and disease severity in rheumatic disease patients. VEGF levels correlated with the presence of Raynaud's phenomenon (P < 0.05), interstitial lung disease (ILD) (P < 0.05), and serum KL-6 levels (P < 0.01), whereas HGF levels correlated with cryoglobulinemia (P < 0.05), ILD (P < 0.05), serum C-reactive protein (CRP) (P < 0.05), thrombomodulin (P < 0.05), and KL-6 levels (P < 0.05) in rheumatic disease patients. VEGF levels correlated with the skin scores and KL-6 levels in SSc patients and also correlated with the disease activity of RA patients. These data suggest that serum VEGF and HGF levels are related to rheumatic disease activity and the presence of complications. Analysis of VEGF and HGF may be useful in the clinical evaluation of rheumatic disease patients.     

Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma

Angiogenesis is a crucial process in the progression of multiple myeloma (MM). Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are multifunctional cytokines that potently stimulate angiogenesis including tumour neovascularization. Serum levels of VEGF and HGF were measured in 52 patients with MM by enzyme-linked immunosorbent assay (ELISA). Serum levels of VEGF and HGF were elevated in MM patients compared with healthy controls (VEGF: mean 0.31 ng/ml and 0.08 ng/ml respectively, P < 0.01; HGF: mean 2.17 ng/ml and 0.45 ng/ml, respectively, P < 0.001). In serial samples taken after chemotherapy, serum VEGF and HGF levels were correlated with M-protein levels. Serum levels of VEGF were higher in patients with extramedullary plasmacytomas than in patients without them (P < 0.05). They were also significantly higher in a group of patients who showed poor response to chemotherapy (P < 0.01). Serum levels of HGF were higher in patients with complications such as anaemia, hypercalcaemia and amyloidosis than in patients without these complications (P < 0.01, P < 0.05, P < 0.05 respectively). Both serum VEGF and HGF levels were significant predictors of mortality (P = 0.01, P = 0.02, respectively, log-rank test). The present study demonstrated that serum levels of VEGF and HGF are significantly elevated and dependent on the severity of MM, suggesting that measurement of VEGF and HGF may be useful for assessing disease progression and for predicting the response to chemotherapy in MM patients.     

Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases

 Angiogenesis plays an important role in the progression of rheumatic disease. We measured the levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in sera from patients with rheumatic diseases and investigated whether these angiogenic factors would be useful in the evaluation of rheumatic diseases. Serum VEGF and HGF levels were determined using ELISA in 128 patients with rheumatic diseases and in 11 healthy controls. Serum VEGF and HGF levels were significantly higher in patients with rheumatic diseases compared to healthy controls [VEGF, 312 ± 20 pg/ml versus 61 ± 8 pg/ml (mean ± SE), P < 0.001; HGF, 935 ± 36 pg/ml versus 413 ± 49 pg/ml, P < 0.01]. Serum VEGF and HGF levels were significantly elevated in patients with adult Still's disease (VEGF, 1021 ± 258 pg/ml; HGF, 1500 ± 295 pg/ml) and were relatively increased in patients with active rheumatoid arthritis (RA) (VEGF, 359 ± 94 pg/ml) and systemic sclerosis (SSc) (VEGF, 356 ± 43 pg/ml; HGF, 1294 ± 224 pg/ml). HGF levels correlated with the clinical course and disease severity in rheumatic disease patients. VEGF levels correlated with the presence of Raynaud's phenomenon (P < 0.05), interstitial lung disease (ILD) (P < 0.05), and serum KL-6 levels (P < 0.01), whereas HGF levels correlated with cryoglobulinemia (P < 0.05), ILD (P < 0.05), serum C-reactive protein (CRP) (P < 0.05), thrombomodulin (P < 0.05), and KL-6 levels (P < 0.05) in rheumatic disease patients. VEGF levels correlated with the skin scores and KL-6 levels in SSc patients and also correlated with the disease activity of RA patients. These data suggest that serum VEGF and HGF levels are related to rheumatic disease activity and the presence of complications. Analysis of VEGF and HGF may be useful in the clinical evaluation of rheumatic disease patients. Received: February 19, 2002 / Accepted: August 13, 2002 Acknowledgment We are grateful to Ms. Aki Nomura for assistance with the ELISA of VEGF and HGF.     

Stimulation in vivo of expression of intra-abdominal adipose tissue plasminogen activator inhibitor Type I by proinsulin

Aims/hypothesis: Impaired fibrinolytic system capacity secondary to increased plasminogen activator inhibitor type-1 expression has been suggested as a pathogenetic link between insulin resistance and increased cardiovascular risk in patients with Type II (non-insulin-dependent) diabetes mellitus, obesity, or both. In patients with syndromes of insulin resistance including those with Type II diabetes, precursors of insulin such as proinsulin can constitute more than 50 % of insulin-like molecules in blood. The aim of this study was to determine whether proinsulin can increase plasminogen activator inhibitor type-1 expression in intra-abdominal adipose tissue in vivo, potentially contributing to the increased PAI-1 seen with insulin resistance. Methods: Lightly sedated normal rabbits were given intravenous proinsulin, insulin, or vehicle alone under euglycaemic clamp conditions with serial sampling of blood and assessment of PAI-1 expression in visceral fat. Results: Both proinsulin and insulin increased expression of plasminogen activator inhibitor type-1 in intra-abdominal adipose tissue, 5.3-fold (p = 0.006 vs control) and 2.5-fold (p = 0.031 vs control) respectively. PAI-1 inhibitor activity in blood peaked 3 h after administration of each, 5.1-fold, p = 0.020, and 3.4-fold, p = 0.004, respectively but did not change under control conditions. Conclusion/interpretation: Hyperproinsulinaemia can contribute to increased expression of plasminogen activator inhibitor type-1 in intra-abdominal adipose tissue implicated in increasing PAI-1 activity in blood, impaired fibrinolysis, and accelerated atherogenesis typical of Type II diabetes. [Diabetologia (2001) 44: 1121–1124] Received: 21 March 2001 and in revised form: 21 May 2001     

Role of endothelial cell survival and death signals in angiogenesis

Angiogenesis, the process of new microvessel development, is encountered in a select number of physiological processes and is central to the pathogenesis of a wide variety of diseases. There is now convincing evidence that regulated patterns of endothelial cell survival and death, a process known as apoptosis, play a central role in the periodic remodeling of the vasculature, and in the timely evolution and regression of angiogenic responses. In this review we discuss the current evidence suggesting a role for inducers and inhibitors of angiogenesis as well as other mediators that modify endothelial cells functions in the survival and death of endothelial cells. We also discuss how dysregulation of apoptosis can lead to aberrant angiogenesis as demonstrated in the pathogenesis of retinopathy of prematurity and cancer. This revised version was published online in June 2006 with corrections to the Cover Date.     

Effect of an aldose reductase inhibitor on type IV collagen production by human endothelial cells cultured in high glucose

Summary Diabetic microangiopathy is characterized by a thickening of capillary basement membranes associated with type IV collagen accumulation. An increase in type IV collagen content of the aortic wall is also observed in macroangiopathy. In order to analyse the importance of the polyol pathway in the development of the collagen metabolism alterations seen in diabetic angiopathy and their prevention by aldose reductase inhibitors, we have studied the effects of sorbinil on the high glucose-induced stimulation of type IV collagen biosynthesis in human umbilical vein endothelial cells. Primary cultures were exposed to high glucose (16.7 mmol/l), with and without 0.11 mmol/l sorbinil, for 3 or 6 days after beginning of confluence. We measured the soluble type IV collagen secreted into the culture medium and the insoluble type IV collagen accumulated in the extracellular matrix and cells, by ELISA. We also studied [¹⁴C]proline incorporation into the newly synthesized collagenous and total proteins in the culture supernatant and in the extracellular matrix and cell fraction. High glucose decreased the number of cells and increased the amount of type IV collagen in the culture supernatant and in the extracellular matrix and cell fraction. It also increased proline incorporation into the newly synthesized collagenous and total proteins in the culture supernatant and in the extracellular matrix and cell fraction. Sorbinil corrected all these high glucose-induced alterations. The corrective effects of sorbinil on the proliferation and on type IV collagen metabolism of endothelial cells cultured in high glucose may be attributed to prevention of polyol pathway dysregulation.Abbreviations AGE Advanced glycation end product - AR aldose reductase - ARI aldose reductase inhibitor - BM basement membrane - EC endothelial cells - GGHG glucosyl-galactosyl-hydroxylysyl-collagen glucohydrolase - HUVEC human umbilical vein EC - HS human serum - PBS phosphate-buffered saline - PKC protein kinase C     

血管内皮细胞生长因子基因多态性与糖尿病肾病的相关性

目的研究血管内皮细胞生长因子（VEGF）基因多态性与糖尿病肾病（DN）的关系。方法单纯2型糖尿病（DM）组76例,DN组81例,健康对照（NC）组60例。UNIQ-10柱提取全血基因组DNA。标本基因型的判断用聚合酶链反应-限制性酶切片断长度多态性技术。Hardy-Weinberg平衡法检验各组基因频率的群体代表性。结果（1）DN组VEGF-460和＋405CC基因型频率和C等位基因频率明显高于DM组和NC组。（2）-460位点CC基因型DN患病率明显高于CT和TT基因型。＋405位点CC基因型DN患病率明显高于CG和GG基因型。（3）显示VEGF-460和＋405基因多态性均为DN发生的独立危险因素。结论（1）VEGF-460C/T基因多态性与DN发生有关。C等位基因可能是DN易感基因。（2）VEGF＋405G/C基因多态性与DN发生有关。C等位基因可能是DN的易感基因。     

Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma

Angiogenesis is a crucial process in growth and progression of cancer and there is growing evidence that neovascularisation is important in hematological malignancies. Since an increased angiogenic potential has been identified in multiple myeloma, we simultaneously measured circulating serum levels of the cytokines bFGF, VEGF, HGF and IL-6 by ELISA in 67 patients with multiple myeloma or monoclonal gammopathies of undetermined significance (MGUS) and in 20 controls. Median values of bFGF were 4.7 pg/ml in healthy volunteers, 6.2 in MGUS, 6.3 in myeloma stage I, 13.4 in stage II and 21.7 in stage III. Myeloma patients had significantly higher bFGF serum levels than controls (p<0.001). Pretreatment bFGF levels differed significantly in the Salmon and Durie stages I-III (p=0.02) and were significantly elevated in stage II-III compared to stage I myeloma (p=0.02). In patients responding to chemotherapy according to the CLMTF criteria, a significant decrease in serum bFGF, VEGF and HGF levels occurred (median pretreatment values for bFGF 23.9 pg/ml, post-treatment 6.5 pg/ml; p<0.001, for VEGF 223 pg/ml versus 105 pg/ml; p=0.02 and for HGF 1429 pg/ml versus 1077 pg/ml; p=0.02, respectively). In 11 patients who did not achieve a remission, there was no significant decrease in bFGF, VEGF and HGF levels. These data show that myeloma in stages II and III is associated with an increase in serum bFGF concentrations and give the first report that effective chemo-therapy is accompanied by a significant decrease in the angiogenic factors bFGF, VEGF and HGF, while no decrease of these factors could be found in nonresponders.     

Role of circulating vascular endothelial growth factor and hepatocyte growth factor in patients with coronary artery disease

Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are thought to stimulate endothelial cell proliferation and induce angiogenesis in vivo. However, the precise mechanism responsible for VEGF and HGF release in patients with coronary artery disease is still unknown. We studied serum concentrations of VEGF and HGF in 20 patients with acute myocardial infarction (AMI), 20 patients with stable angina pectoris (AP) who had reversible perfusion defects on stress myocardial scintigraphy, and 16 patients with old myocardial infarction (OMI) who had no reversible defects on stress myocardial scintigraphy. The control group consisted of 20 patients with atypical chest pain who had angiographically normal coronary arteries. Serum VEGF and HGF concentrations were measured by enzyme-linked immunosorbent assay. Both the serum VEGF and HGF concentrations in the early stage of myocardial infarction in the patients with AMI were higher than those in the patients with AP and with OMI, and control patients. The VEGF concentration in the patients with AP was higher than in the patients with OMI, whereas the HGF concentration did not differ in the patients with AP and OMI. The VEGF concentration in AMI patients who had had preinfarction angina on admission was higher than that of patients who had had no preinfarction angina, whereas the HGF concentration did not differ between the two groups of patients. These results suggest that the serum VEGF concentration may reflect myocardial ischemia to a greater degree than the serum HGF concentration. Received June 9, 2000 / Accepted September 30, 2000     

Role of vascular endothelial growth factor (VEGF) and placenta-derived growth factor (PlGF) in regulating human haemopoietic cell growth

Vascular endothelial growth factor (VEGF) and placental derived growth factor (PlGF) stimulate cell proliferation and differentiation by binding to their specific receptors, Flk-1/KDR and Flt-1 respectively. Flk-1/KDR-deficient murine embryos manifest failure of blood-island formation and vasculogenesis. The aim of this study was to directly evaluate the importance of VEGF, PlGF/Flt-1 and Flk-1/KDR receptor ligand interactions in regulating normal and malignant human haemopoiesis. Addition of VEGF and PlGF failed to enhance survival or cloning efficiency of human haemopoietic progenitors isolated from adult bone marrows, fetal livers or cord blood samples. This finding may be explained by the apparent absence of mRNA encoding Flt-1 and Flk-1/KDR receptors on stem cell rich CD34⁺ c-kit-R⁺ Rh123^low cells. Further studies revealed that Flt-1 R mRNA, but not Flk-1/KDR mRNA was first detectable in the more mature cells isolated from haemopoietic colonies. Accordingly, VEGF receptors are either absent, or expressed at very low level, on human haemopoietic stem/progenitor cells. Of interest, normal and malignant human haemopoietic cells appeared to secrete VEGF protein. However, in contrast to normal haemopoietic progenitors, VEGF co-stimulated HEL cell proliferation as well as CFU-GM colony formation from ∼15% of the chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) patients studied. Therefore, although VEGF appeared to have minimal effects on normal haemopoietic cell growth it would appear to drive malignant haemopoietic cell proliferation to some degree. Of more importance, however, we speculate that VEGF may play an very important role in leukaemogenesis by stimulating growth of vascular endothelium, thereby providing a sufficient blood supply to feed the growing haematological tumour.     

血管内皮生长因子、血小板源性生长因子-BB与2型糖尿病患者血糖波动及微血管病变的关系

目的观察糖化血红蛋白（HbAlC）〈7．0％的2型糖尿病患者血糖波动与糖尿病微血管病变（视网膜病变、糖尿病肾病）及血清血管内皮生长因子（VEGF）、血小板源性生长因子-BB（PDGF—BB）水平之间的关系,探讨其在HbAlC达标患者中的相互影响机制。方法选取2010年10月至2012年8月在黑龙江省医院内分泌科就诊的2型糖尿病患者100例,其中男52例、女48例,年龄40～66岁。根据是否合并糖尿病微血管病变分为单纯2型糖尿病组[A组,n=30,男14例,女16例,年龄（50±11）岁],糖尿病肾病组[B组,n=38,男20例,女18例,年龄（52±10）岁]和糖尿病视网膜病变组[C组,n=32,男18例,女14例,年龄（53±13）岁]。另以同期于黑龙江省医院进行体检的25名健康者为正常对照组[Con组,n=25,男12例,女13例,年龄（48±9）岁]。人院前糖尿病患者均使用药物治疗。所有参试者均测定空腹血糖浓度（FPG）、总胆固醇（TC）、甘油i酯（TG）、低密度脂蛋白胆同醇（LDL—C）、高密度脂蛋白胆固醇（HDL—C）、餐后2h血糖浓度（2hPG）、24h尿微量白蛋白（24h尿ALB）和HbAlc。应用动态血糖监测系统连续监测血糖3d,计算平均血糖（MBG）、平均血糖标准差（SDBG）、平均血糖波动幅度（MAGE）、日内最大血糖波动幅度（LAGE）、日间血糖平均绝对差（MODD）和曲线下面积（AUC）。采用酶联免疫吸附法分别检测血清中VEGF和PDGF—BB水平。计量资料组间比较采用t检验,多组间比较采用单因素方差分析,糖尿病微血管并发症的影响因素采用logistic回归分析,PDGF．BB、VEGF相关因素采用多元线性回归分析。结果（1）B组PDGF—BB水平高于A组和Con组[分别为（53±12）、（31±6）、（26±4）μg／ml,F=9．56,P〈0．05];C组VEGF水平高于A组和Con组[分别为（217±57）、（105±12）、（74±10）μg／ml,F=8．13,P〈0．05]。（2）动态血糖监测指标B组与A组比较,SDBG、LAGF、MAGE、MODD、AUC明显升高（t=2．57、3．46、5．75、3．59、4．28,均P〈0．05）,C组与A组比较,SDBG、LAGF、MAGE、MODD、AUC明显升高（t=3．29、3．77、5．38、4．54、3．16,均P〈0．05）,而MBG在3组间的差异无统计学意义,均P〉0．05。（3）logistic回归分析显示PDGF-BB、VEGF及血糖波动是糖尿病微血管并发症独立危险因素。分别以PDGF-BB、VEGF为因变量,以血糖波动指标SDBG、LAGF、MAGE、MODD、AUC及2hPG为自变量,采用多元线性回归分析可能影响PDGF-BB、VEGF的相关因素,结果显示,MAGE、SDBG和2hPG对PDGF-BB、VEGF影响最大。结论2型糖尿病患者微血管病变的发生发展与血糖波动具有明显相关性,血糖波动可导致血清血管内皮生长因子和血小板源性生长因子-BB水平增高,从而参与糖尿病视网膜病变、糖尿病肾病等微血管病变的进展。     

Expression of vascular endothelial growth factor in sera and lymph nodes of the plasma cell type of Castleman's disease

To evaluate the possible involvement of vascular endothelial growth factor (VEGF) in the pathogenesis of Castleman's disease, we studied VEGF levels in sera and supernatants of cultured lymph nodes from two patients with the plasma cell type of Castleman's disease, and analysed the expression of VEGF immunohistochemically in the lymph nodes. Clinically, one patient was classified as the localized type and the other as the multicentric type. Histologically, mature plasma cells and hyalinized vessels were prominent in the interfollicular region. The VEGF levels of the sera and the supernatants of cultured lymph nodes of both patients were higher than those of normal controls. VEGF was strongly expressed in plasma cells in the interfollicular region of the lymph nodes of both patients, but rarely in normal lymph nodes. Our results suggest that VEGF may be involved in the marked vascular proliferation in the interfollicular region of the lymph nodes of the plasma cell type of Castleman's disease.     

Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195

Aims/hypothesis. Advanced glycation end products (AGEs) participate in the pathogenesis of diabetic nephropathy. We reported earlier that OPB-9195, a synthetic thiazolidine derivative and novel inhibitor of advanced glycation, prevented progression of diabetic glomerulosclerosis by lowering serum concentrations of advanced glycation end products and reducing their deposition in the glomeruli. Here, we examined their contribution and that of growth factors, such as transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF), to the progression of diabetic nephropathy. We also investigated the expression of type IV collagen in the kidneys of Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a Type II (non-insulin-dependent) diabetes mellitus model, after treatment with OPB-9195. Methods. Using northern blots and immunohistochemical techniques, we determined the renal expression of TGF-β and type IV collagen mRNAs and proteins in OLETF rats. We also examined OPB-9195's effects on renal expression of VEGF mRNA and protein. Results. Concomitant increases in TGF-β and type IV collagen expression were observed at each point in time in OLETF rats not given OPB-9195. In contrast, OPB-9195 treatment greatly suppressed the renal expression of TGF-β, VEGF and type IV collagen mRNAs and proteins to that seen in non-diabetic rats. Conclusion/interpretation. Since OPB-9195, an AGE-inhibitor, prevented the progression of diabetic nephropathy by blocking type IV collagen production and suppressing overproduction of two growth factors, TGF-β and VEGF, in diabetic rats, this compound warrants further investigation. [Diabetologia (1999) 42: 579–588] Received: 2 October 1998 and in final revised form: 28 December 1998     

The regulation and consequences of immune-mediated cell death in atheromatous diseases

Atheromatous diseases are lipid and cell-rich vascular disorders that include coronary artery disease (CAD), transplant vascular disease (TVD), and restenosis. Considering the inflammatory nature of these diseases, cytotoxic immune mechanisms such as the FasL and granzyme/perforin pathways most likely play important roles in the development and remodeling of many lesions. Furthermore, although the contributions of immune responses to each disease vary, the correspondent localization of certain mediators and effectors suggests that they may contribute to a spectrum of atheromatous diseases. In this review, the contribution of immune cell-mediated cell death in the onset and pathogenesis of CAD and TVD is examined.     

Serum and intraocular concentrations of erythropoietin and vascular endothelial growth factor in patients with type 2 diabetes and proliferative retinopathy

AimThis study compared systemic and intraocular concentrations of erythropoietin (EPO) and vascular endothelial growth factor (VEGF) in patients with type 2 diabetes (T2D) and proliferative diabetic retinopathy (PDR) with levels in patients without diabetes, and looked for possible correlations between the concentrations found and other variables analyzed.MethodsConcentrations of EPO and VEGF were measured in the aqueous and vitreous humours and serum of patients undergoing vitrectomy for PDR (33 patients) or for macular holes or puckers (20 control patients). EPO was assayed by radioimmunoassay, with a lower limit of detection (LOD) of 1.0 mIU/mL. VEGF was assayed using enzyme-linked immunosorbent assay (ELISA), with a lower LOD of 10.0 pg/mL.ResultsEPO concentrations in serum did not differ significantly between the two groups, whereas EPO in vitreous and aqueous were higher in diabetic than in non-diabetic patients. VEGF in serum was lower in diabetic patients than in non-diabetics; conversely, VEGF concentrations in vitreous were significantly higher in diabetic patients. A direct correlation was found between vitreous and aqueous EPO concentrations, and between vitreous EPO and blood glucose concentrations. A significant, negative correlation between vitreous EPO concentration and age was also recorded.ConclusionHigh EPO concentrations in the vitreous of patients with PDR and its correlation with blood glucose suggest that EPO could play a role in the pathogenesis of PDR. All possible factors affecting serum and ocular concentrations of EPO and VEGF should be determined to identify compounds able to prevent and control this serious microvascular complication of diabetes.     

血管内皮生长因子基因3'-非翻译区C936T多态性与2型糖尿病肾病相关

采用PCR-RFLP方法分析了194例2型糖尿病患者血管内皮生长因子(VECF)基因3'-非翻译区C936T变异与糖尿病肾病的关系.发现糖尿病肾病组C等位基因及CC基因型频率显著高于非肾病组和正常对照组,提示C等位基因及CC基因型患者可能是糖尿病易于发生肾病危险性的遗传标志.     

Soluble endothelial protein C receptor and high sensitivity C reactive protein levels as markers of endothelial dysfunction in patients with type 1 and type 2 diabetes mellitus: Their role in the prediction of vascular complications

Background and objectiveEndothelial dysfunction in diabetes mellitus (DM) is an important factor in the pathogenesis of micro and macrovascular complications. We aimed to measure soluble endothelial protein C receptor (sEPCR) and high sensitivity C reactive protein (hsCRP) levels as markers of endothelial damage in both types of diabetes mellitus and to determine if they can be used as predictors of vascular complications.MethodsFifty patients with DM, 20 with type 1 and 30 with type 2 as well as 30 healthy subjects were included. All were subjected to measurement of sEPCR and hsCRP by enzyme linked immunosorbent assay.ResultssEPCR and hsCRP were significantly increased when compared to the control group in both types of DM. sEPCR was a significant predictor of macrovascular complications and thrombosis in type 1 p = 0.02, and p = 0.015, respectively. hsCRP was a significant predictor of macrovascular complications in type 2 p = 0.04.ConclusionPatients with type 1 and type 2 DM exhibit higher sEPCR and hsCRP levels compared to healthy controls which suggesting endothelial damage. sEPCR could be used as a predictor of macrovascular complications and thrombosis in type 1 DM, whereas, hsCRP might be used as a predictor of macrovascular complications in type 2 DM.