Transforming Growth Factor (TGF)-beta is markedly induced and rapidly activated in the infarcted myocardium. However, understanding of the exact role of TGF-beta signaling in the infarcted and remodeling heart has been hampered by the complex and unusual biology of TGF-beta activation and by the diversity of its effects eliciting multiple, and often opposing cellular responses. Experimental studies suggest that TGF-beta signaling may be crucial for repression of inflammatory gene synthesis in healing infarcts mediating resolution of the inflammatory infiltrate. In addition, TGF-beta may play an important role in modulating fibroblast phenotype and gene expression, promoting extracellular matrix deposition in the infarct by upregulating collagen and fibronectin synthesis and by decreasing matrix degradation through induction of protease inhibitors. TGF-beta is also a key mediator in the pathogenesis of hypertrophic and dilative ventricular remodeling by stimulating cardiomyocyte growth and by inducing interstitial fibrosis. In this review we summarize the current knowledge on the role of TGF-beta in infarct healing and cardiac remodeling.

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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 proinflammatory cytokine interleukin (IL)-1 signals exclusively through the type I IL-1 receptor (IL-1RI). IL-1 expression is markedly induced in the infarcted heart; however, its role in cardiac injury and repair remains controversial. We examined the effects of disrupted IL-1 signaling on infarct healing and cardiac remodeling using IL-1RI؊/؊ mice. After reperfused infarction IL-1RI-null mice exhibited decreased infiltration of the infarcted myocardium with neutrophils and macrophages and reduced chemokine and cytokine expression. In the absence of IL-1 signaling, suppressed inflammation was followed by an attenuated fibrotic response. Infarcted IL-1RI ؊/؊ mice had decreased myofibroblast infiltration and reduced collagen deposition in the infarcted and remodeling myocardium. IL-1RI deficiency protected against the development of adverse remodeling; however, infarct size was comparable between groups suggesting that the beneficial effects of IL-1RI gene disruption were not attributable to decreased cardiomyocyte injury. Reduced chamber dilation in IL-1RI-null animals was associated with decreased collagen deposition and attenuated matrix metalloproteinase (MMP)-2 and MMP-3 expression in the peri-infarct area, suggesting decreased fibrotic remodeling of the noninfarcted heart. IL-1␤ stimulated MMP mRNA synthesis in wild-type, but not in IL-1RI-null cardiac fibroblasts. In conclusion, IL-1 signaling is essential for activation of inflammatory and fibrogenic pathways in the healing infarct, playing an important role in the pathogenesis of remodeling after infarction. Thus, interventional therapeutics targeting the IL-1 system may have great benefits in myocardial infarction. Infarct healing is dependent on induction of an inflammatory cascade that ultimately results in formation of a collagen-based scar.1 The healing response is closely intertwined with ventricular remodeling, a complex process that involves both the infarcted and noninfarcted myocardium resulting in dilation, hypertrophy, and enhanced sphericity of the ventricle. 2 The extent of remodeling after infarction is an important predictor of mortality and adverse outcome after infarction, 3,4 and depends on the size of the infarct and on the mechanical and structural characteristics of the healing wound. Inflammatory mediators may be critically involved in the pathogenesis of cardiac remodeling by modulating cell behavior in the infarcted heart and by regulating extracellular matrix metabolism. 5-7Interleukin (IL)-1 plays a central role in regulating inflammatory and fibrotic responses by inducing synthesis of proinflammatory mediators, by promoting leukocyte infiltration and activation, and by modulating fibroblast function. IL-1 binds to two distinct receptors on the cell membrane: the type I IL-1 receptor (IL-1RI) is sufficient to mediate all IL-1 actions, 8 whereas the type II receptor (IL-1RII) serves as a decoy target, 9 trapping and scavenging IL-1 molecules, 10 thus reducing IL-1 concentration available for interaction with the IL-1RI signa...

Myocardial infarction triggers an inflammatory reaction that is involved in cardiac remodeling. Cardiac repair is dependent on regulatory mechanisms that suppress inflammation and prevent excessive matrix degradation. Chemokine induction in the infarcted heart mediates recruitment of leukocyte subsets with distinct properties. We demonstrate that signaling through the CC chemokine receptor 5 (CCR5) prevents uncontrolled postinfarction inflammation and protects from adverse remodeling by recruiting suppressive mononuclear cells. CCR5 and its ligands macrophage inflammatory protein (MIP)؊1␣ and MIP-1␤ were markedly induced in the infarcted mouse myocardium. In addition, almost 40% of the mononuclear cells infiltrating the infarct expressed CCR5. CCR5؊/؊ mice exhibited marked upregulation of proinflammatory cytokine and chemokine expression in the infarct. In wildtype infarcts CCR5؉ mononuclear cells had antiinflammatory properties, expressing higher levels of IL-10 than CCR5 ؊ cells. In contrast, mononuclear cells isolated from CCR5 ؊/؊ infarcts had reduced IL-10 expression. Moreover, enhanced inflammation in the absence of CCR5 was associated with impaired recruitment of CD4 ؉ /foxp3؉ regulatory T cells (Tregs). The CCR5 ؉ Treg subset exhibited increased IL-10 expression, reflecting potent anti-inflammatory activity. Accentuated inflammation in CCR5 ؊/؊ infarcts was associated with increased matrix metalloproteinase (MMP) expression, reduced TIMP levels, and enhanced MMP-2 and MMP-9 activity, resulting in worse cardiac dilation. These results suggest that CCR5-mediated Treg recruitment may restrain postinfarction inflammation, preventing excessive matrix degradation and attenuating adverse remodeling.