Response to the Letter by Sovari and Dudley
In response to the Letter by Sovari and Dudley, we agree with their proposal that increased transforming growth factor (TGF)-β expression correlates with increased myocardial fibrosis and may serve as a useful prognostic marker for the development of myocardial fibrosis ultimately resulting in heart failure. However, we also feel that additional research must be performed to thoroughly examine the risk stratification potential of TGF-β, considering the vast number of signaling networks involved, as well as the contribution of other signaling pathways that lead to fibrosis, collagen deposition, and extracellular matrix turnover. We cited one example of signaling pathway crosstalk in our review.1 Following induction of hypertrophy, Smad3, a key protein in the TGF-β signaling cascade, was phosphorylated by protein kinase G. This phosphorylation resulted in inhibition of TGF-β-mediated Smad3 activation, preventing myofibroblast transformation, proliferation, and extracellular matrix production.
In agreement with Sorvari and Dudley, it has been shown that the appearance of myofibroblasts in the infarct scar is preceded by an increase in TGF-β2; however, there is no direct link demonstrating TGF-β-mediated proliferation. In fact, recent studies from Petrov and colleagues demonstrated that cardiac fibroblasts treated with TGF-β differentiated irreversibly into nonproliferating myofibroblasts.3 Moreover, it has been demonstrated in other systems that TGF-β can inhibit proliferation, as well as promote either cell survival or apoptosis.4,5
When discussing the effects of specific proteins on the heart, studies performed in vitro must be included with those performed in vivo, because many signaling factors are difficult to delineate and examine in vivo. Many of the conflicting phenomena observed in vitro have not yet been directly examined in vivo. Our review included several in vivo and in vitro studies pertaining to the role of TGF-β in fibrosis and heart failure, and we agree that it was weighted with in vitro observations. We are unaware how the study by Klein et al6 relates to these discussions, because in the article, the authors only addressed increased TGF-β levels correlating with an increase in collagen I deposition, not cell proliferation; however, this article was not cited in our review,7 as indicated in the Letter by Sovari and Dudley.
Again, we do not disagree that TGF-β is an important predictor of future cardiac function; we merely note that additional studies are needed to clarify the potential roles of TGF-β on cellular phenotypes and that these studies would provide more specific targets for diagnosis, prevention, and treatment of heart failure following injury.
Sources of Funding
Supported by NIH grant R01 HL85847.
Li P, Wang D, Lucas J, Oparil S, Xing D, Cao X, Novak L, Renfrow MB, Chen YF. Atrial natriuretic peptide inhibits transforming growth factor β-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ Res. 2008; 102: 185–192.
Sun Y, Weber KT. Infarct scar: a dynamic tissue. Cardiovasc Res. 2000; 46: 250–256.
Souders CA, Bowers SL, Baudino TA. Cardiac fibroblast: the renaissance cell. Circ Res. 2009; 105: 1164–1176.