tranilast and Diabetic-Angiopathies

The pathological accumulation of extracellular matrix is a characteristic feature of diabetic cardiomyopathy that is directly related to a loss of function. Tranilast (n-[3,4-anthranilic acid), used for the treatment of fibrotic skin diseases, has also been shown to inhibit transforming growth factor-beta (TGF-beta)-induced matrix production in kidney epithelial cells.. To investigate the effects of tranilast in the diabetic heart, we examined its effects in cultured cardiac fibroblasts and then assessed its effects in (mRen-2)27 diabetic rats with established disease (8 weeks after streptozotocin).. In vitro studies demonstrated a 58% reduction in TGF-beta1-induced 3[H]-hydroxyproline incorporation with tranilast 30 microM (p<0.01). At 16 weeks, diabetes in the Ren-2 rat was associated with increased cardiac fibrosis and evidence of TGF-beta1 activation, as measured by the abundance of phosphorylated Smad2. Despite persistent hyperglycaemia and hypertension, tranilast attenuated cardiac fibrosis by 37% (p<0.05) in association with reduction in phospho-Smad2 (p<0.01).. These findings indicate that tranilast has antifibrotic actions in the Ren-2 model of experimental diabetic cardiac disease by mechanisms that might attributable to reduced TGF-beta activity.

Topics: Animals; Collagen; Diabetes Mellitus, Experimental; Diabetic Angiopathies; DNA-Binding Proteins; Extracellular Matrix; Female; Fibroblasts; Fibrosis; Heart; Myocardium; ortho-Aminobenzoates; Phosphorylation; Rats; Smad2 Protein; Trans-Activators; Transforming Growth Factor beta; Transforming Growth Factor beta1

Diabetic patients undergoing coronary interventions have worse clinical and angiographic outcomes than do patients without diabetes. Metformin, an insulin sensitizer, may decrease the occurrence of these outcomes. Diabetic patients in the Prevention of Restenosis with Tranilast and its Outcomes Trial were identified through their medical records (n = 2,772). In this trial, 1,110 diabetic patients received nonsensitizer therapy (insulin and/or sulfonylureas) and 887 received sensitizer therapy (metformin with or without additional therapy). Logistic regression was used to obtain odds ratios (ORs) (sensitizer vs nonsensitizer therapy) of any clinical event (death, myocardial infarction, or ischemia-driven target vessel revascularization) and adjusted for multiple risk factors. Multivariate analysis showed no effect of lesion characteristics on clinical outcomes. Compared with patients on nonsensitizer therapy, those on sensitizer therapy showed an adjusted OR of 0.72 (95% confidence interval [CI] 0.57 to 0.91, p = 0.005) for any clinical event. The differences between the nonsensitizer therapy group and the sensitizer group were attributable mainly to decreased rates of death (OR 0.39, 95% CI 0.19 to 0.77, p = 0.007) and myocardial infarction (OR 0.31, 95% CI 0.15 to 0.66, p = 0.002). In our retrospective analysis, use of metformin in diabetics undergoing coronary interventions appeared to decrease adverse clinical events, especially death and myocardial infarction, compared with diabetic patients treated with nonsensitizer therapy.

Topics: Angioplasty, Balloon, Coronary; Case-Control Studies; Coronary Restenosis; Databases, Factual; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Female; Humans; Hypoglycemic Agents; Logistic Models; Male; Metformin; Middle Aged; Myocardial Infarction; ortho-Aminobenzoates; Platelet Aggregation Inhibitors; Proportional Hazards Models; Randomized Controlled Trials as Topic; Retrospective Studies

The growth factors transforming growth factor-B (TGF-B) and epidermal growth factor (EGF) have both been implicated in the hypertrophic structural changes in the vasculature that are characteristic features of both human and experimental diabetes. Recently, tranilast (N(3,4-dimethoxycinnamoyl)anthranilic acid), a drug used in the treatment of allergic and dermatological diseases, has also been reported to inhibit transforming growth factor-B (TGF-B)-mediated collagen formation. However, its effects on vascular hypertrophy in diabetes are unknown. The present study thus sought to determine the effects of tranilast on both TGF-B and EGF expression and mast cells in mediating the trophic vascular changes in experimental diabetes.. Vessel morphology, growth factors and collagen gene expression and matrix deposition were examined in the mesenteric arteries of control rats treated with or without tranilast, and streptozotocin-induced diabetic Sprague-Dawley rats treated with or without tranilast (200 mg/kg/day) during a 3-week period.. Compared with control animals, diabetic rats had significantly increased vessel weight, wall: lumen ratio, ECM accumulation, gene expression of TGF-B1, EGF, and both alpha1 (I) and alpha1 (IV) collagen. Tranilast treatment did not influence plasma glucose or systemic blood pressure. However, tranilast significantly reduced mesenteric weight, wall: lumen ratio and matrix deposition and also attenuated the overexpression of TGF-B1, EGF, and both alpha1 (I) and alpha1 (IV) collagen mRNA in diabetic rats.. These findings indicate that tranilast ameliorates pathological vascular changes observed in experimental diabetes in association with reduced growth factor expression independent of blood glucose or systemic blood pressure.

Topics: Animals; Base Sequence; Blood Vessels; Collagen; Diabetes Mellitus, Experimental; Diabetic Angiopathies; DNA Primers; Epidermal Growth Factor; Gene Expression Regulation; Growth Substances; Hypertrophy; Immunohistochemistry; Male; ortho-Aminobenzoates; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta