News Volume 10, Issue 9 pp 2230—2232

Aging, cardiac repair and Smad3

Figure 1. Age-related accentuation of adverse post-infarction remodeling may be due to an impaired response of reparative fibroblasts to TGF-β. Our observations suggest that: a) myofibroblast-specific loss of Smad3 disrupts scar organization, increasing adverse remodeling following myocardial infarction, b) senescent hearts exhibit impaired infarct healing, accompanied by decreased collagen deposition, and c) fibroblasts harvested from senescent hearts exhibit blunted Smad2/3 activation in response to TGF-β stimulation. Taken together these observations suggest the intriguing hypothesis that age-associated impairment in TGF-β/Smad signaling in reparative fibroblasts may reduce tensile strength of the healing scar, accentuating adverse remodeling following infarction and causing heart failure. Several mechanisms may account for reduced TGF−β responses in senescent cardiac fibroblasts. Age-associated alterations of the expression of signaling TGF-β receptors (TβRI and TβRII) and pseudoreceptors (such as BAMBI) may modulate the response to TGF-β. Activation of phosphatases or induction of inhibitory Smad7, such as Smad7 may attenuate Smad2/3 activation in response to TGF-β. Because aging is associated with baseline activation of a fibrogenic program (that may involve low level increase in basal TGF-β activity), TGF-β-driven induction of endogenous signals that inhibit Smad-dependent signaling may be responsible for blunted responses to the sudden burst in TGF-β activity observed following cardiac injury.