Aging, cardiac repair and Smad3

The adult mammalian myocardium lacks endogenous regenerative capacity; thus, following myocardial infarction, the heart heals through formation of a collagen-based scar. Cardiac repair is dependent on a superbly orchestrated inflammatory cascade that sequentially recruits inflammatory cells, fibroblasts and vascular cells in the infarct zone. Expansion of fibroblast populations in the infarcted myocardium and conversion into activated myofibroblasts play a critical role in infarct healing, maintaining the structural integrity of the ventricle and preventing cardiac rupture. However, exaggerated myofibroblast activation may promote excessive deposition of extracellular matrix proteins in the infarct border zone and in the viable remodeling myocardium, precipitating heart failure [1]. Members of the Transforming Growth Factor (TGF)-β superfamily have been implicated in activation of fibroblasts in healing and remodeling tissues. TGF-βs act by transducing signaling cascades mediated through a series of intracellular effectors the Smads, or through Smad-independent pathways. Smad2/3 signaling is activated in all cell types involved in cardiac repair [2, 3], and may modulate inflammatory, reparative and remodeling responses. Cell-specific effects of Smad3 signaling in the infarcted myocardium In a recently published study, we generated cell-specific Smad3 knockout mice, in order to investigate the role of Smad3 signaling in regulating fibroblast and cardiomyocyte function following myocardial infarction [4]. We found that cardiomyocyte Smad3 signaling has no effects on cardiac homeostasis, but promotes cardiomyocyte apoptosis and accentuates dilative remodeling, enhancing matrix metalloproteinase expression, and increasing nitrosative stress following myocardial infarction. In contrast, Smad3 signaling in activated infarct myofibroblasts is protective, restraining fibroblast proliferation and contributing to scar organization by stimulating integrin-dependent interactions between the fibroblasts and the extracellular matrix In the infarcted myocardium, myofibroblasts are organized in arrays, exhibiting alignment along the direction of the ventricular wall. Myofibroblast-specific loss of Smad3 perturbs alignment of myofibroblast arrays in the infarct, leading to formation of a disorganized scar. Disturbances in scar formation in myofibroblast-specific News