Adenovirus-mediated overexpression of TIMP-1, -2, -3, and -4 in cardiac fibroblasts provoked a significant 1.3-fold increase in BrdU incorporation (P < 0.0001).
Does overexpression of TIMPs affect proliferation, differentiation, collagen synthesis, and apoptosis in isolated cardiac fibroblasts?
TIMPs stimulate cardiac fibroblast proliferation and differentiation into myofibroblasts independently of MMP inhibition, suggesting a direct role in cardiac tissue repair.
Effect estimate: 1.3-fold increase
p-value: p=< 0.0001
The balance between matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), plays a critical role in cardiac remodeling. Although a number of studies have characterized the pathophysiological role of MMPs in the heart, very little is known with respect to the role of TIMPs in the heart. To delineate the role of TIMPs in the heart we examined the effects of adenovirus-mediated overexpression of TIMP-1, -2, -3, and -4 in cardiac fibroblasts. Infection of cardiac fibroblasts with adenoviral constructs containing human recombinant TIMP (AdTIMP-1, -2, -3, and -4) provoked a significant (P < 0.0001) 1.3-fold in increase in bromodeoxyuridine (BrdU) incorporation. Similarly, treatment of cardiac fibroblasts with AdTIMP-1-, -2-, -3-, and -4-conditioned medium led to a 1.2-fold increase in BrdU incorporation (P < 0.0001) that was abolished by pretreatment with anti-TIMP-1, -2, -3, and -4 antibodies. The effects of TIMPs were not mimicked by treating the cells with RS-130830, a broad-based MMP inhibitor, suggesting that the effects of TIMPs were independent of their ability to inhibit MMPs. Infection with AdTIMP-1, -2, -3, and -4 led to a significant increase in alpha-smooth muscle actin staining, consistent with TIMP-induced phenotypic differentiation into myofibroblasts. Finally, infection with AdTIMP-2 resulted in a significant increase in collagen synthesis, whereas infection with AdTIMP-3 resulted in a significant increase in fibroblast apoptosis. TIMPs exert overlapping as well as diverse effects on isolated cardiac fibroblasts. The observation that TIMPs stimulate fibroblast proliferation as well as phenotypic differentiation into myofibroblasts suggests that TIMPs may play an important role in tissue repair in the heart that extends beyond their traditional role as MMP inhibitors.
Lovelock et al. (Thu,) conducted a other in Cardiac remodeling. Adenovirus-mediated overexpression of TIMP-1, -2, -3, and -4 was evaluated on Bromodeoxyuridine (BrdU) incorporation (1.3-fold increase, p=< 0.0001). Adenovirus-mediated overexpression of TIMP-1, -2, -3, and -4 in cardiac fibroblasts provoked a significant 1.3-fold increase in BrdU incorporation (P < 0.0001).