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)

Emerging evidence now indicates that the 5-lipoxygenase (5-LO) pathway play a role in the pathogenesis of atherosclerosis and restenosis. The expression of 5-LO by activated macrophages in symptomatic plaques leads to leukotriene B(4) (LTB(4)) accumulation and enhanced synthesis and release of matrix metalloproteinases (MMPs) that can promote plaque rupture. However, the role of 5-LO pathway in diabetic vascular disease has not been previously reported. Thus, the present study was designed to analyze the expression of 5-LO in carotid plaques of diabetic patients and to investigate the possible role of 5-LO pathway in the pathogenesis and progression of diabetic atherosclerosis. Atherosclerotic plaques from 60 patients undergoing carotid endarterectomy were divided into non-diabetic and diabetic group. Plaques were analyzed for 5-LO, MMP-2 and MMP-9 by immunohistochemical, Western blot, and densitometric analyses, whereas zymography was used to detect MMP activity. Immunocytochemistry was also used to identify CD68+macrophages, CD3+T-lymphocytes, and HLA-DR+inflammatory cells. LTB(4) were quantified by enzyme-linked immunosorbent assay. 5-LO showed abundant immunoreactivity in human atherosclerotic carotid lesions, and was colocalized with macrophage infiltrates in atherosclerotic intima. 5-LO expression was higher in diabetic compared with non-diabetic plaques and was associated with increased MMP-2 and MMP-9 expression. Follow-up analyze with zymography assay revealed MMP activity was elevated in diabetic compared with non-diabetic plaques. Notably, in contrast to non-diabetic plaques, LTB(4) levels were significantly increased in diabetic plaques by enzyme-linked immunosorbent assay. These results suggest that overexpression of 5-LO and LTB(4) in atherosclerotic plaques possibly promote MMP-induced plaque rupture in diabetes. Hence, anti-LTs may be useful, not only in reducing atherogenesis, but also in the prevention and treatment of acute atherothrombotic events in diabetic patients.
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PMID:Expanding expression of the 5-lipoxygenase/leukotriene B4 pathway in atherosclerotic lesions of diabetic patients promotes plaque instability. 1782 94

The authors hypothesized that matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 would be abnormal in acute coronary syndromes (ACS). Forty-six diabetic and 78 nondiabetic patients during ACS and after 3 months were enrolled in this study. MMP-2, -9 and TIMP-1, -2 plasma levels were measured. Significant decrease of MMP-2, TIMP-1, and TIMP-2 plasma levels was observed in the nondiabetic group with ACS after 3 months compared to the baseline value. Significant decrease of MMP-2, MMP-9, TIMP-1, and TIMP-2 plasma levels was observed in the diabetic group with ACS after 3 months compared to the baseline value. MMP-9, TIMP-1, and TIMP-2 plasma levels were higher in diabetic patients during ACS compared to nondiabetic patients during ACS. TIMP-1 and TIMP-2 increases were observed in diabetic patients with ACS at 3 months compared to nondiabetic patients after ACS. MMPs and TIMP-1 and -2 plasma levels were alterated in nondiabetic and diabetic patients during ACS and after 3 months, which may reflect abnormal extracellular matrix metabolism in diabetes during and after acute event.
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PMID:Metalloproteinases in diabetics and nondiabetics during acute coronary syndromes and after 3 months. 1792 33

We hypothesized that matrix metalloproteinase (MMP)-2, -9, and tissue inhibitor metalloproteinase-1, -2 (TIMP-1, -2) would be abnormal in diabetes and in acute coronary syndromes (ACS). We measured MMP-2, -9, and TIMP-1, -2 plasma levels in healthy subjects (controls), in type 2 diabetic patients, in nondiabetic patients with ACS (ACS) and in diabetic patients with ACS (DACS). We enrolled 165 controls, 181 diabetic patients, 78 ACS, and 46 DACS. We measured also BMI (body mass index), HbA(1c) (glycated hemoglobin) FPG (fasting plasma glucosa), FPI (fasting plasma insulin), HOMA index (homeostasis model assessment index), SBP (systolic blood pressure), DBP (diastolic blood pressure), TC (total cholesterol), LDL-C (low density lipoprotein cholesterol), HDL-C (high-density lipoprotein cholesterol), Tg (triglycerides), Lp(a) (lipoprotein(a)) PAI-1 (plasminogen activator inhibitor-1), Hct (homocysteine), Fg (fibrinogen), and hs-CRP (high-sensitivity C-reactive protein). A significant increase of BMI was observed in the diabetic group, in ACS and DACS patients compared to controls. A significant increase of SBP and DBP resulted in the diabetic and DACS groups, while only SBP improvement was present in ACS patients with respect to controls. A decrease in SBP and DBP was observed in the ACS group, while SBP variation was present in DACS patients compared to diabetics, and DBP increase was obtained in the DACS group with respect to ACS patients. TC, LDL-C, Tg, and Lp(a) increase was present in diabetics, while TC, Tg, and Lp(a) improvement was present in ACS and DACS patients with a significant decrease of HDL-C levels in diabetic, ACS, and DACS groups compared to controls. A decrease in LDL-C was obtained in ACS and DACS groups, while HDL-C increase was observed in these patients with respect to diabetics. Tg levels were higher in the DACS group compared to diabetics and ACS patients, respectively. Increases in PAI-1, Hct, Fg, and hs-CRP were present in diabetic and DACS groups, while PAI-1, Hct, and hs-CRP improvement was obtained in ACS patients with respect to controls. Higher PAI-1 levels came about in ACS and DACS groups, while HCT and Fg levels were lower in ACS patients compared to diabetics. An increase in Fg was present in the DACS group with respect to ACS patients. A decrease in Hs-CRP was observed in DACS patients compared to diabetics and the ACS group, respectively. Higher MMP-2, MMP-9, TIMP-1, and TIMP-2 levels were present in diabetic, ACS, and DACS patients compared to controls. Significant MMP-2, TIMP-1, and TIMP-2 increases were observed in ACS and DACS groups, while MMP-9 decreased in these patients compared to diabetics. In conclusion, MMP-2, MMP-9, TIMP-1, and TIMP-2 plasma levels were higher in diabetic, ACS, and DACS patients, which may reflect abnormal extracellular matrix metabolism in diabetes and in acute coronary syndrome.
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PMID:Comparison between metalloproteinases-2 and -9 in healthy subjects, diabetics, and subjects with acute coronary syndrome. 1804 92

Suppressed parasympathetic nervous system (PSNS) function has been found in a variety of cardiovascular diseases, such as hypertension, heart failure, and diabetes. However, whether impaired PSNS function plays a significant role in ventricular dysfunction remains to be investigated. Cardiac regulation by the PSNS is primarily mediated by the M(2) muscarinic acetylcholine receptor (M(2)-AChR). In this study, we tested the hypothesis that lack of M(2)-AChR-mediated PSNS function may adversely impact cardiac ventricular function. Using M(2)-AChR knockout (KO) and wild-type (WT) mice, we found that the basal levels of heart rate and left ventricular function were similar in M(2)-AChR KO and WT mice. A bolus injection of isoproterenol (Iso) induced a greater increase in heart rate in M(2)-AChR KO mice than in WT mice. However, the responses of change in pressure over time (dP/dt) to Iso were similar in the two groups. After chronic infusion with Iso for 1 wk, the baseline values of left ventricular function were increased to similar extents in M(2)-AChR KO and WT mice. However, the M(2)-AChR KO mice exhibited impaired ventricular function, indicated as attenuated dP/dt and increased end-diastolic pressure, during an increase in cardiac afterload induced by a bolus injection of phenylephrine. Furthermore, chronic Iso infusion significantly increased matrix metalloproteinase (MMP) activity in the heart in M(2)-AChR KO mice. In primary culture of mixed neonatal rat cardiac fibroblast and cardiomyocytes, cotreatment with muscarinic agonist bethanechol reversed phenylephrine-induced increase in MMP-9 activation. These data suggest that M(2)-AChR may mediate an inhibitory regulation on MMP function. The overall results from this study suggest that M(2)-AChR-mediated PSNS function may provide cardiac protection. Lack of this protective mechanism will increase the susceptibility of the heart to cardiac stresses.
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PMID:Deficiency of M2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress. 1805 17

Independent of the severity of coronary artery disease, diabetic patients have an increased risk of developing heart failure. Diabetic cardiomyopathy (DCM) is characterized by microvascular pathologies and interstitial fibrosis. Mesenchymal stem cells (MSCs) are pluripotent and are able to differentiate into cardiomyocytes and vascular endothelial cells. Studies have demonstrated MSCs transplantation can prevent apoptosis of ischemic heart via upregulation of Akt and eNOS and inhibit myocardial fibrosis of dilated cardiomyopathy by decreasing the expression of matrix metalloproteinase (MMP) in rat models. In order to find out whether transplantation of MSCs is a promising treatment in DCM, we used streptozotocin (STZ) -induced diabetic rats as the model. Exogenous MSCs were injected into the femoral vein 8 weeks after STZ injection. Using independent experimental approaches, we showed that MSCs presented in the myocardium 4 weeks after transplantation and some of them were positive for the cardiac markers Troponin T and myosin heavy chain. MSCs transplantation significantly increased myocardial arteriolar density and decreased the collagen volume in diabetic myocardium resulting in improved cardiac function. Furthermore, MSCs transplantation increased MMP-2 activity and decreased transcriptional level of MMP-9. These results show that MSCs transplantation improved cardiac function in the rat DCM model, possibly through angiogenesis and attenuation of cardiac remodeling.
Exp Clin Endocrinol Diabetes 2008 Feb
PMID:Bone marrow mesenchymal stem cells induce angiogenesis and attenuate the remodeling of diabetic cardiomyopathy. 1828 26

In diabetic nephropathy decreased activities of matrix metalloproteinase (MMP)-2, MMP-9 and plasmin contribute to mesangial matrix accumulation. Megsin, a novel member of the serine protease inhibitor superfamily, is predominantly expressed in mesangial cells and is up-regulated in diabetic nephropathy and its overexpression spontaneously induces progressive mesangial expansion in mice. High-glucose stimulated megsin mRNA expression in an in vivo model of type II diabetic nephropathy as well as in vitro in cultured mesangial cells. Megsin potentially inhibits total enzymatic activities of MMP-2 and -9 and plasmin, indicating decreased degradation of mesangial matrix. A specific monoclonal anti-megsin neutralizing antibody restored MMP activity in a transforming growth factor-beta independent manner. Our study suggests that the mesangial matrix accumulation caused by hyperglycemia in diabetes might be due at least in part to up-regulation of megsin which can inhibit plasmin and MMP activities.
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PMID:The role of megsin, a serine protease inhibitor, in diabetic mesangial matrix accumulation. 1858 Aug 57

Recent diabetes control and complications trial and epidemiology of diabetes interventions and complications (DCCT/EDIC) and other clinical studies have reported that glucose control in patients with diabetes leads to a significant reduction of cardiovascular events and atherosclerosis, indicating that hyperglycemia plays an essential role in cardiovascular disease in diabetic patients. Although several mechanisms by which hyperglycemia promotes atherosclerosis have been proposed, it remains unclear how hyperglycemia promotes atherosclerosis by interaction with inflammatory cytokines. To test our hypothesis that hyperglycemia interplays with interferon gamma (IFN gamma), a key factor involved in atherosclerosis, to up-regulate the expression of genes such as matrix metalloproteinases (MMPs) and cytokines that are involved in plaque destabilization, U937 macrophages cultured in medium containing either normal or high glucose were challenged with IFN gamma and the expression of MMPs and cytokines were then quantified by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Results showed that high glucose and IFN gamma had a synergistic effect on the expression of MMP-1, MMP-9 and IL-1 beta. High glucose also enhanced IFN gamma-induced priming effect on lipopolysaccharide (LPS)-stimulated MMP-1 secretion. Furthermore, high glucose and IFN gamma exert the synergistic effect on MMP-1 expression by enhancing STAT1 phosphorylation and STAT1 transcriptional activity. In summary, this study revealed a novel mechanism potentially involved in diabetes-promoted cardiovascular disease.
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PMID:High glucose and interferon gamma synergistically stimulate MMP-1 expression in U937 macrophages by increasing transcription factor STAT1 activity. 1858 52

Endothelial progenitor cells (EPC) significantly contribute to neovascularization and endothelial regeneration. Risk factors for coronary artery disease, particularly diabetes mellitus, reduce the number and functional activity of EPC. As we have recently shown, expression and activity of the matrix degrading cysteine protease cathepsin L in EPC is required for tissue invasion and EPC-mediated improvement of neovascularization. Therefore, we investigated the effect of high glucose and diabetes mellitus on EPC invasion and cathepsin L activity. Incubation of EPC with high levels of glucose (10-30 mM) dose-dependently decreased cathepsin L activity (glucose 20 mM: 67+/-4% compared to control; p<0.05) and protein expression (48+/-5% of control, p<0.05). In contrast, other proteases of the cathepsin family such as cathepsins D and O, and the matrix metalloproteinases MMP-2 and MMP-9 were not altered with high glucose. Cathepsin L mRNA was not affected suggesting that a posttranscriptional mechanism is responsible for cathepsin L down-regulation. As a functional consequence, high glucose significantly reduced the gelatinolytic activity and invasion of EPC (50+/-5% of control). Importantly, EPC of patients with type 2 diabetes revealed profoundly decreased cathepsin L expression and activity as compared to EPC derived from healthy controls. Taken together, high glucose significantly reduces the protein expression and activity of cathepsin L, which is involved in matrix degradation and required for invasion of EPC into the ischemic tissue, and, thereby, may limit the functional capacity of EPC to improve neovascularization in diabetics.
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PMID:High glucose reduces cathepsin L activity and impairs invasion of circulating progenitor cells. 1861 73

Matrix metalloproteinases (MMPs) comprise a family of over 20 structurally related proteins which are zinc-dependent and calcium-activated endopeptidases. The members of this family are able to degrade most extracellular matrix (ECM) proteins and are thus involved in tissue remodeling and contribute to cell migration by eliminating extracellular matrix and basement membrane barriers. Of the MMPs, MMP-2 and MMP-9 are especially active in the degradation of type IV collagen, the main constituent of the basement membrane. MMPs also cleave a variety of non-ECM proteins, including cytokines, chemokines, and growth factors. MMPs and their inhibitors (TIMPs) play important roles in physiological processes such as embryogenesis and wound healing; however, these enzymes are also involved in the pathogeneses of many diseases, such as cancer and atherosclerosis. In these pathological conditions the balance between MMPs and TIMPs shifts in favor of MMPs, resulting in excessive degradation of ECM. Research results published recently show that these enzymes can also be involved in the pathogenesis of diabetes mellitus and diabetic complications such as diabetic retinopathy. MMP-9 has the ability to degrade insulin and is able to activate IL-8, the main chemoattractant factor for neutrophils and monocytes. In addition, MMP-9 enables infl ammatory cell migration and pancreas colonization by eliminating the basement membrane barriers. Type IV collagenases are also important for endothelial cell invasion occurring during neovascularization (diabetic retinopathy), as angiogenesis needs extracellular matrix degradation; what is more, these enzymes are able to degrade pigment epithelium-derived factor, which is the principal antiangiogenic protein of the eye.
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PMID:[The role of matrix metalloproteinases in the pathogenesis of diabetes mellitus and progression of diabetes retinopathy]. 1877 49

Diabetes and hyperhomocysteinemia (HHcy) are two independent risk factors for glomeruloslerosis and renal insufficiency. Although PPARgamma agonists such as ciglitazone (CZ) are known to modulate diabetic nephropathy, the role of CZ in diabetes-associated HHcy and renopathy is incompletely defined. We tested the hypothesis that induction of PPARgamma by CZ decreases tissue Hcy level; this provides a protective role against diabetic nephropathy. C57BL/6J mice were administered alloxan to create diabetes. Mice were grouped to 0, 1, 10, 12, and 16 wk of treatment; only 12- and 16-wk animals received CZ in drinking water after a 10-wk alloxan treatment. In diabetes, PPARgamma cDNA, mRNA, and protein expression were repressed, whereas an increase in plasma and glomerular Hcy levels was observed. CZ normalized PPARgamma mRNA and protein expression and glomerular level of Hcy, whereas plasma level of Hcy remained unchanged. GFR was dramatically increased at 1-wk diabetic induction, followed by hypofiltration at 10 wk, and was normalized by CZ treatment. This result corroborated with glomerular and preglomerular arteriole histology. A steady-state increase of RVR in diabetic mice became normal with CZ treatment. CZ ameliorated decrease bioavailability of NO in the diabetic animal. Glomerular MMP-2 and MMP-9 activities as well as TIMP-1 expression were increased robustly in diabetic mice and normalized with CZ treatment. Interestingly, TIMP-4 expression was opposite to that of TIMP-1 in diabetic and CZ-treated groups. These results suggested that diabetic nephropathy exacerbated glomerular tissue level of Hcy, and this caused further deterioration of glomerulus. CZ, however, protected diabetic nephropathy in part by activating PPARgamma and clearing glomerular tissue Hcy.
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PMID:Ciglitazone, a PPARgamma agonist, ameliorates diabetic nephropathy in part through homocysteine clearance. 1878 Jul 70


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