Thrombospondin-1 Induction in the Diabetic Myocardium Stabilizes the Cardiac Matrix in Addition to Promoting Vascular Rarefaction Through Angiopoietin-2 Upregulation

• DOI: 10.1161/circresaha.113.302593
• Publication Date: 2013-10-01T05:57:33Z
• Authors: Carlos Gonzalez-Q...; Michele Cavalera; Anna Biernacka; Ping Kong; Dong-Wook Lee; Amit Saxena; Olga Frunza; Marcin Dobaczewski; Arti Shinde; Nikolaos G. Frang...
• Keywords: Matricellular protein; Thrombospondin 1; Periostin; Angiopoietin; Cardiac Fibrosis

Diabetes mellitus is associated with cardiac fibrosis. Matricellular proteins are induced in fibrotic conditions and modulate fibrogenic angiogenic responses by regulating growth factor signaling.Our aim was to test the hypothesis that prototypical matricellular protein thrombospondin (TSP)-1, a potent angiostatic molecule crucial activator of transforming factor-β, may play key role remodeling diabetic heart.Obese db/db mice exhibited marked myocardial TSP-1 upregulation interstitial perivascular space. To study heart, we generated characterized TSP-1(-/-) (dbTSP) mice. disruption did not significantly affect weight gain metabolic function animals. When compared animals, dbTSP had increased left ventricular dilation mild nonprogressive systolic dysfunction. Chamber decreased collagen content accentuated matrix metalloproteinase-2 -9 activity. inflammatory gene expression activation factor-β/small mothers against decapendaplegic signaling myocardium. In fibroblasts populating pads, incorporation into activate factor-β responses, but inhibited leptin-induced activation. abrogated age-associated capillary rarefaction mice, attenuating angiopoietin-2, mediator induces vascular regression. vitro, stimulation macrophage, endothelial cell, angiopoietin-2 synthesis.TSP-1 heart prevents chamber exerting matrix-preserving actions on mediates through effects involve upregulation.