Induction of Thrombospondin (TSP)‐1 and Tissue Transglutaminase (tTG) in the Infarct Border Zone May Limit Expansion of Granulation Tissue Formation

Abstract

Effective infarct healing depends on granulation tissue formation in the infarcted area and on mechanisms preventing expansion of the inflammatory reaction to normal areas. The border zone of healing myocardial infarcts may contain factors limiting expansion of the inflammatory process to the normal area. In both canine and mouse infarcts, TSP-1, a potent TGF-β activator, and tTG, a cross-linking enzyme with a key role in TGF-β activation, were selectively expressed in the extracellular matrix and microvascular endothelium of the border zone after 1-7 days of reperfusion. Infarcted TSP-1 knockout mice exhibited sustained chemokine and cytokine upregulation, suggesting an enhanced and prolonged inflammatory response. TSP-1 KOs had increased macrophage and myofibroblast density in infarcts and in remodeling non-infarcted myocardial areas neighboring the myocardial scar, suggesting expansion of granulation tissue formation into the non-infarcted territory. TSP-1 −/− infarcted hearts exhibited decreased smad2 phosphorylation compared with WT hearts, suggesting defective activation of TGF-β signaling pathways. Although infarct size was similar in both groups, TSP-1 deficient animals had enhanced post-infarction remodeling. We suggest that, through its unique composition, the infarct border zone may serve as a barrier limiting expansion of the inflammatory reaction. (NIH R01 HL-76246, AHA)