Abstract 17049: Upregulation of the Matricellular Protein Thrombospondin (TSP)-1 in the db/db Heart Regulates Matrix Remodeling and Induces Vascular Rarefaction

The matricellular protein Thrombospondin (TSP)-1, a potent angiostatic agent and crucial TGF-β activator, is markedly upregulated in animal models of obesity and diabetes and in tissues from diabetic patients; however, its role in the pathogenesis of diabetic complications is unknown. Leptin resistant db/db mice rapidly develop obesity and diabetes and exhibit cardiac hypertrophy, fibrosis and diastolic dysfunction as they age. We hypothesized that TSP-1 induction in the db/db heart may regulate cardiac remodeling and fibrosis. TSP-1 expression was markedly upregulated in db/db hearts. In order to dissect the role of TSP-1 in diabetic cardiomyopathy we generated db/db TSP-1 -/- (dbTSP-1) mice and we studied the effects of TSP-1 absence on the metabolic and cardiac dysfunction associated with central leptin resistance. TSP-1 absence did not affect weight gain and fat content in db/db mice. Mortality was comparable between db/db and dbTSP-1 mice. dbTSP-1 mice had significant alterations in chamber geometry exhibiting increased left ventricular dilation (LVEDV, db/db:73.36+2.03 vs. dbTSP1:90.14+5.85 p<0.01) associated with a modest deterioration in systolic function (FS, db/db: 41.82+1.07 vs. dbTSP1:31.02+1.59 p<0.01). In order to dissect the mechanisms responsible for chamber dilation in dbTSP-1 mice, we examined the effects of TSP-1 absence on matrix remodeling. Using a hydroxyproline assay, we found that TSP-1 loss reduced collagen deposition in db/db animals. Decreased cardiac fibrosis in dbTSP-1 mice was associated with diminished TGF-β/Smad3 signaling and attenuated MMP activity in the myocardium. Moreover, db/db hearts exhibited an aging-associated vascular rarefaction in the myocardium that was attenuated in dbTSP-1 animals (capillary density, WT: 4311.6+313.17 vs. db/db: 2994+133 vs. dbTSP1 3659.1+60.9 p<0.01). Our findings demonstrate that, while inducing TGF-β activation and cardiac fibrosis, TSP-1 induction in obese diabetic hearts plays a role in maintaining matrix homeostasis, thus protecting the myocardium from dilative remodeling. Moreover, TSP-1 upregulation is, at least in part, responsible for reduced angiogenesis in the hypertrophied diabetic heart, leading to formation of a rarefied capillary network.