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

Abstract

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

The extracellular matrix in myocardial injury, repair, and remodeling

“…Fibrotic changes in diabetic hearts are, at least in part, independent of coronary artery disease or hypertension (121), reflecting direct effects of metabolic dysregulation on the ECM. Diabetes, obesity, and metabolic dysfunction are associated with activation of cardiac fibroblasts (122) and are accompanied by deposition of matricellular macromolecules (123) and progressive accumulation of fibrillary collagens in the cardiac interstitium (124,125). The molecular basis for activation of the so-called diabetic fibroblast remains unknown.…”

The role of transforming growth factor (TGF)-β in the infarcted myocardium

“…In the absence of TSP-1, expansion of inflammatory activation increases fibrosis and accentuates adverse remodeling (41). However, it should be emphasized that TSP-1 has multiple cellular targets and several functional domains and may regulate inflammation and fibrosis through TGF-β-independent effects (64).…”

Fluorescence Microangiography for Quantitative Assessment of Peritubular Capillary Changes after AKI in Mice

“…This mouse FMA approach should be useful for the study of the microvasculature, not just in the kidney but in a variety of solid organs, where capillary rarefaction after injury is also considered to be an important component of chronic disease progression. [27][28][29] It should also enable a more precise definition of changes within the interstitial space that accompany injury and repair, such as visualizing pericyte migration away from endothelium during CKD, which has been proposed to underlie fibrogenesis. 19 …”