Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Delayed wound healing and accelerated atherosclerosis are common vascular complications of diabetes mellitus. Although elevated blood glucose level is the major contributing factor, mechanisms that mediate these complications are not clearly understood. In the present study, we have demonstrated that elevated glucose inhibits endothelial cell migration, thereby delaying wound healing. Our results clearly indicated that high glucose (10 or 30 mM) induced activation of nuclear factor kappa B (NF-kappaB) inhibited endothelial cell migration (P<0.05). High glucose induced NF-kappaB DNA binding activity may mediate this inhibition of migration by regulating intracellular nitric oxide. In vitro wound healing model in human aortic endothelial cells (HAEC) were used to evaluate cell migration under the influence of high glucose. The migration inhibited by high glucose was restored by NF-kappaB inhibitors (including E3-4-methylphenyl sulfonyl-2-propenenitrile, N-tosyl-Lys-chloromethylketone (TLCK), or over-expression of inhibitor subunit of kappaB) and endothelial nitric oxide synthase inhibitors (N-methyl-L-arginine (L-NMMA); and Nomega-nitro-L-arginine methyl ester (L-NAME)). Furthermore, NF-kappaB inhibitors attenuated high glucose induced eNOS expression and intracellular nitric oxide (NO) production. Cytoskeletal immunofluorescence staining confirmed differences in actin distribution in HAEC incubated in high glucose in the presence or absence of NF-kappaB and NO inhibitors, explaining the differences observed in migration. In summary, our results for the first time suggest therapeutic strategies involving inhibition of NF-kappaB activation induced by high glucose, which may improve wound healing and help avoid some of the vascular complications of diabetes.
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PMID:High glucose induced nuclear factor kappa B mediated inhibition of endothelial cell migration. 1199 47

Diabetic retinopathy remains a leading cause of irreversible blindness. A critical early pathology in the disease is the adhesion of leukocytes to the retinal vasculature, a process that occurs, in part, via intercellular adhesion molecule-1. Once leukocyte adhesion occurs, endothelial cell injury ensues, as does blood-retinal barrier breakdown. Here we show that angiopoietin-1 can prevent and reverse these diabetic retinal vascular changes in both new and established diabetes. Angiopoietin-1, when given intravitreally to newly diabetic rats, normalized retinal vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 mRNA and protein levels, leading to reductions in leukocyte adhesion, endothelial cell injury, and blood-retinal barrier breakdown. When an adenovirus coding for angiopoietin-1 was given systemically to mice with established diabetes, it similarly inhibited leukocyte adhesion and endothelial cell injury and blood-retinal barrier breakdown. These changes coincided with reductions in retinal eNOS, nitric oxide, Akt (protein kinase B), and MAP kinase activity, known mediators of VEGF bioactivity and leukocyte adhesion. When endogenous VEGF bioactivity was inhibited with a soluble Flt-1/Fc chimera, retinal Akt kinase activity was significantly reduced in vivo. Taken together, these data document new vascular and anti-inflammatory bioactivities for angiopoietin-1 and identify it as the first naturally occurring protein that directly protects the retinal vasculature in diabetes.
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PMID:Suppression of diabetic retinopathy with angiopoietin-1. 1200 Jul 4

Diabetic vasculopathy is central to the development of diverse cardiovascular, renal, retinal, and neurological complications of diabetes. We previously demonstrated that growth of endothelial cells on glycated extracellular matrix proteins (collagen and matrigel) results in a significant decrease in cell proliferation. In the present study, we show that early-passage human umbilical vein endothelial cells (HUVECs) grown on glycated collagen (GC) express hallmarks of premature cell senescence, ie, increase in the proportion of cells expressing senescence-associated beta-galactosidase activity, apoptotic rate, and p53 and p14(AFR) expression, but in contrast to replicative senescence, display neither attrition of telomeres nor decrease in telomerase activity. An increased frequency of prematurely senescent cells was similarly observed in vivo in aortae of young Zucker diabetic rats, compared with lean controls. NO production by HUVECs grown on GC was decreased, despite a 3-fold increase in eNOS expression and was associated with the increased nitrotyrosine-modified proteins. Development of premature senescence of HUVECs on GC could be prevented and reversed by treatments with the peroxynitrite scavenger, ebselen, eNOS intermediate N(omega)-hydroxy-L-arginine (NOHA), or superoxide dismutase mimetic Mn-TBAP. Concomitant with the reversal of senescence, ebselen, and NOHA each restored NO production to levels observed with HUVECs grown on unmodified collagen. Our findings indicate that diabetes mellitus in vivo and GC exposure in vitro elicit premature senescence of the vascular endothelium, a process with distinct pathogenetic mechanisms. Premature senescence of the vascular endothelium is hypothesized to be an important contributor to diabetic vasculopathy and a consequence of reduced NO availability, peroxynitrite, and/or superoxide excess.
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PMID:Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells. 1208 67

The functional role of the NO synthase (NOS) isoforms in the normal or diseased kidney is uncertain. This study examined the renal expression of the endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) isoforms by both immunohistochemistry and Western blot analyses in sham-operated rats (S) and in rats subjected to 5/6 nephrectomy (Nx). Primary antibodies from two different sources were used to detect iNOS. Additional S and Nx rats were chronically treated with aminoguanidine (AG), a selective iNOS inhibitor. All three isoforms were clearly expressed in S kidney. Their renal abundance, evaluated by Western blot analysis, fell in Nx rats. With the use of anti-iNOS antibodies from two distinct sources, the immunohistochemical analysis showed the presence of what appeared to be two distinct iNOS fractions: a "tubular" fraction, present in S and with decreased intensity in Nx; and an "interstitial" fraction, observed only in inflamed areas of Nx rats. AG treatment greatly attenuated renal injury in Nx rats by a direct antiinflammatory effect, likely related to iNOS inhibition, rather than to amelioration of renal hemodynamics or to reduced protein glycation. These observations suggest that: (1) the functional role of the renal iNOS isoform may vary dramatically under different physiologic conditions; (2) caution should be taken in the interpretation of immunohistochemical iNOS data, because antibodies from different sources may detect different iNOS fractions; and (3) AG treatment may become useful in the treatment of human progressive nephropathies, even those not associated with diabetes or aging.
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PMID:Evidence for the existence of two distinct functions for the inducible NO synthase in the rat kidney: effect of aminoguanidine in rats with 5/6 ablation. 1219 72

Gene therapy refers to the transfer of specific genes to the host tissue to intervene in a disease process, with resultant alleviation of the symptoms of a particular disease. Cardiovascular gene transfer is not only a powerful technique for studying the function of specific genes in cardiovascular biology and pathobiology, but also a novel and promising strategy for treating cardiovascular diseases. Since the mid-1990s, nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide (NO) from L-arginine, has received considerable attention as a potential candidate for cardiovascular gene therapy, because NO exerts critical and diverse functions in the cardiovascular system, and abnormalities in NO biology are apparent in a number of cardiovascular disease processes including cerebral vasospasm, atherosclerosis, postangioplasty restenosis, transplant vasculopathy, hypertension, diabetes mellitus, impotence and delayed wound healing. There are three NOS isoforms, i.e., endothelial (eNOS), neuronal (nNOS) and inducible (iNOS). All three NOS isoforms have been used in cardiovascular gene transfer studies with encouraging results. This review will discuss the rationale of NOS gene therapy in different cardiovascular disease settings and summarize the results of experimental NOS gene therapy from various animal models of cardiovascular disease to date.
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PMID:Nitric oxide synthase gene therapy for cardiovascular disease. 1223 10

Migration of endothelial cells (EC) is a key event in angiogenesis that contributes to neovascularization in diabetic vasculopathy. Leptin induces angiogenesis and is elevated in obesity and hyperinsulinemia. The antidiabetic thiazolidinediones (TZD) inhibit leptin gene expression and vascular smooth muscle cell migration through activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma). This study investigates the role of leptin in EC migration, the chemotactic signaling pathways involved, and the effects of the TZD-PPARgamma ligands troglitazone (TRO) and ciglitazone (CIG) on EC migration. We demonstrate that leptin induces EC migration. Because activation of two signaling pathways, the phosphatidylinositol-3 kinase (PI3K)-->Akt-->eNOS and the ERK1/2 MAPK pathway, is known to be involved in cell migration, we used the pharmacological inhibitors wortmannin and PD98059 to determine if chemotactic signaling by leptin involves Akt or ERK1/2, respectively. Both wortmannin and PD98059 significantly inhibited leptin-induced migration. Treatment with the TZD-PPARgamma-ligands TRO and CIG significantly inhibited the chemotactic response toward leptin. Both PPARgamma-ligands inhibited leptin-stimulated Akt and eNOS phosphorylation, but neither attenuated ERK 1/2 activation in response to leptin. The inhibition of Akt-phosphorylation was accompanied by a PPARgamma-ligand-mediated upregulation of PTEN, a phosphatase that functions as a negative regulator of PI3K-->Akt signaling. These experiments provide the first evidence that activation of Akt and ERK 1/2 are crucial events in leptin-mediated signal transduction leading to EC migration. Moreover, inhibition of leptin-directed migration by the PPARgamma-ligands TRO and CIG through inhibition of Akt underscores their potential in the prevention of diabetes-associated complications.
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PMID:Leptin induces endothelial cell migration through Akt, which is inhibited by PPARgamma-ligands. 1241 72

While transport processes for amino acids and glucose have long been known to be expressed in the luminal and abluminal membranes of the endothelium comprising the blood-brain and blood-retinal barriers, it is only within the last decades that endothelial and smooth muscle cells derived from peripheral vascular beds have been recognized to rapidly transport and metabolize these nutrients. This review focuses principally on the mechanisms regulating amino acid and glucose transporters in vascular endothelial cells, although we also summarize recent advances in the understanding of the mechanisms controlling membrane transport activity and expression in vascular smooth muscle cells. We compare the specificity, ionic dependence, and kinetic properties of amino acid and glucose transport systems identified in endothelial cells derived from cerebral, retinal, and peripheral vascular beds and review the regulation of transport by vasoactive agonists, nitric oxide (NO), substrate deprivation, hypoxia, hyperglycemia, diabetes, insulin, steroid hormones, and development. In view of the importance of NO as a modulator of vascular tone under basal conditions and in disease and chronic inflammation, we critically review the evidence that transport of L-arginine and glucose in endothelial and smooth muscle cells is modulated by bacterial endotoxin, proinflammatory cytokines, and atherogenic lipids. The recent colocalization of the cationic amino acid transporter CAT-1 (system y(+)), nitric oxide synthase (eNOS), and caveolin-1 in endothelial plasmalemmal caveolae provides a novel mechanism for the regulation of NO production by L-arginine delivery and circulating hormones such insulin and 17beta-estradiol.
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PMID:Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. 1250 30

Increased reduction of glucose via the polyol pathway enzyme aldose reductase (AR) has been linked to the development of secondary diabetic complications. Because AR is a redox-sensitive protein, which in vitro is readily modified by NO donors, we tested the hypothesis that NO may be a physiological regulator of AR. We found that administration of the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) increased sorbitol accumulation in the aorta of nondiabetic and diabetic rats, whereas treatment with L-arginine (a precursor of NO) or nitroglycerine patches prevented sorbitol accumulation. When incubated ex vivo with high glucose, sorbitol accumulation was increased by L-NAME and prevented by L-arginine in strips of aorta from rats or wild-type, but not eNOS-deficient, mice. Exposure to NO donors also inhibited AR and prevented sorbitol accumulation in rat aortic vascular smooth muscle cells (VSMC) in culture. The NO donors also increased the incorporation of radioactivity in the AR protein immunoprecipitated from VSMC in which the glutathione pool was prelabeled with [35S]-cysteine. Based on these observations, we suggest that NO regulates the vascular synthesis of polyols by S-thiolating AR; therefore, increasing NO synthesis or bioavailability may be useful in preventing diabetes-induced changes in the polyol pathway.
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PMID:Nitric oxide regulates the polyol pathway of glucose metabolism in vascular smooth muscle cells. 1263 81

Coronary and valvular heart disease during diabetes mellitus (DM) are major contributors of morbidity and mortality in the diabetic population. Relatively little atention has been given to the study of heart valve nerve structures in different pathological processes. In this study we have demonstrated the presence of possible morphological alterations in vessels of the anterior cusp of the rat mitral valve during 8-12 weeks DM. A histochemical method was used for the detection of NADPH-diaphorase (NADPH-d), which is the indirect NO-synthase marker. Arterioles and fine capillaries were localized in the attachment zone of the anterior cusp. Perivascular nerve fibres were identified running in the tunica adventitia. A marked dilatation of the vessels was seen in diabetes in comparison with control samples. No NADPH-d positive nerve fibres were observed in the tunica adventitia. It can be presumed that metabolic changes in the vessel walls during DM reflect modified neurotransmission of NO by means of their excessive overproduction of NOS (endothelial--eNOS) in endothelial cells. (Fig. 6, Ref. 32.).
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PMID:Alterations of the vessel wall innervation during diabetes mellitus. 1269 74

As an important modulator of renal function and morphology, the nitric oxide (NO) system has been extensively studied in the diabetic kidney. However, a number of studies in different experimental and clinical settings have produced often confusing data and contradictory findings. We have reviewed a wide spectrum of findings and issues that have amassed concerning the pathophysiology of the renal NO system in diabetes, pointed out the controversies, and attempted to find some explanation for these discrepancies. Severe diabetes with profound insulinopenia can be viewed as a state of generalized NO deficiency, including in the kidney. However, we have focused our hypotheses and conclusions on the events occurring during moderate glycemic control with some degree of treatment with exogenous insulin, representing more the clinically applicable state of diabetic nephropathy. Available evidence suggests that diabetes triggers mechanisms that in parallel enhance and suppress NO bioavailability in the kidney. We hypothesize that during the early phases of nephropathy, the balance between these two opposing forces is shifted toward NO. This plays a role in the development of characteristic hemodynamic changes and may contribute to consequent structural alterations in glomeruli. Both endothelial (eNOS) and neuronal NO synthase can contribute to altered NO production. These enzymes, particularly eNOS, can be activated by Ca(2+)-independent and alternative routes of activation that may be elusive in traditional methods of investigation. As the duration of exposure to the diabetic milieu increases, factors that suppress NO bioavailability gradually prevail. Increasing accumulations of advanced glycation end products may be one of the culprits in this process. In addition, this balance is continuously modified by actual metabolic control and the degree of insulinopenia.
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PMID:Paradoxes of nitric oxide in the diabetic kidney. 1273 64


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