Essential Role of Smad3 in Infarct Healing and in the Pathogenesis of Cardiac Remodeling

Abstract

Background-Postinfarction cardiac repair is regulated through timely activation and repression of inflammatory pathways, followed by transition to fibrous tissue deposition and formation of a scar. The transforming growth factor-␤/Smad3 pathway is activated in healing infarcts and may regulate cellular events critical for the inflammatory and the fibrotic responses. Methods and Results-We examined the effects of Smad3 gene disruption on infarct healing and the pathogenesis of cardiac remodeling. In the absence of injury, Smad3-null hearts had comparable function to and similar morphology as wild-type hearts. Smad3-null animals had suppressed peak chemokine expression and decreased neutrophil recruitment in the infarcted myocardium but showed timely repression of inflammatory gene synthesis and resolution of the inflammatory infiltrate. Although myofibroblast density was higher in Smad3-null infarcts, interstitial deposition of collagen and tenascin-C in the remodeling myocardium was markedly reduced. Compared with wild-type animals, Smad3 Ϫ/Ϫ mice exhibited decreased dilative remodeling and attenuated diastolic dysfunction; however, infarct size was comparable between groups. Transforming growth factor-␤-mediated induction of procollagen type III and tenascin-C in isolated cardiac fibroblasts was dependent on Smad3, which suggests that decreased fibrotic remodeling in infarcted Smad3-null hearts may be due to abrogation of the profibrotic transforming growth factor-␤ responses. Conclusions-Smad3 loss does not alter the time course of resolution of inflammation in healing infarcts, but it prevents interstitial fibrosis in the noninfarcted myocardium and attenuates cardiac remodeling. Thus, the Smad3 cascade may be a promising therapeutic target for the treatment of myocardial infarction.

The immune system and cardiac repair

“…Thus, in the absence of Smad3 signaling the infarct was filled with a large number of dysfunctional fibroblasts. Attenuated fibrosis on the non-infarcted heart in Smad3 −/− mice was associated with reduced dilative remodeling and improved diastolic function; however infarct size was comparable between groups [311]. Our findings suggested that Smad3 loss does not alter the time course of resolution of inflammation in healing infarcts, but prevents interstitial fibrosis in the noninfarcted myocardium and attenuates cardiac remodeling.…”

“…TGF-β expression in the infarcted heart is attenuated by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers [306], [307], [308], suggesting that angiotensin II signaling plays an important role in stimulating TGF-β synthesis in the infarct [309]. TGF-β expression is predominantly localized in the infarct border zone, associated with expression of Smad2, 3 and 4 [310] and phosphorylation of Smad1 and Smad2 [311]. Although evidence suggests that bioactive TGF-β is released in the cardiac extracellular fluids 3-5h following reperfused infarction [32], the mechanisms responsible for TGF-β activation in the infarcted heart are poorly understood.…”

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

“…In the infarcted heart, evidence suggesting the presence of bioactive TGF-β in cardiac extracellular fluids (37), and activation of downstream Smad-dependent signaling (38) suggest rapid activation of TGF-β. The mechanisms responsible for TGF-β activation following infarction remain poorly understood.…”

TGF-β signaling in vascular biology and dysfunction

“…TGF-β is a crucial regulator of cardiac remodeling through its direct and potent actions in mediating cardiomyocyte growth, fibroblast activation and extracellular matrix deposition [106].…”