Abstract
The molecular pathways that couple increased hemodynamic load to cardiac hypertrophy, cardiac fibrosis, and heart failure are incompletely understood. Cardiac fibrosis is recognized as a major disease modifier and as such is important in the pathogenesis of heart failure of most etiologies. This review is focused on R-Smad signaling in cardiac myofibroblasts and their role in remodeling the extracellular matrix of the failing myocardium after myocardial infarction (MI). As major mediators of TGF-β1 signaling in cardiac fibroblasts and myofibroblasts as well as myocytic cells, Smad proteins are emerging as an important postreceptor class in post-MI heart failure. How cytosolic c-Ski and C184M proteins influence R-Smads (and possibly Smad7 itself) in cardiac myofibroblasts, and how c-Ski expression influences cardiac myofibroblast function are largely unknown. We suggest that decreased Smad7 expression and altered intracellular c-Ski expression and/or distribution may contribute to chronic imbalance of R-Smad activation in classic TGF-β1 signaling in the context of cardiac myofibroblast function. Thus, reduced and insufficient expression and activation of c-Ski and Smad7 may contribute to abnormal stimulation of collagen synthesis by these cells. Exploitation of Smad7 and c-Ski in the modulation of cardiac myofibroblast function may provide the experimental basis for the development of highly specific drugs for treating heart failure with attendant cardiac fibrosis. Future studies to identify and characterize Smad-associated factors responsible for induction of pathological cardiac hypertrophy are warranted.
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Dixon, I.M.C., Wang, B., Bedosky, K.M., Cunnington, R.H., Rattan, S.G., Almaqrhi, A. (2008). Regulatory Role of TGF-β in Cardiac Myofibroblast Function and Post-MI Cardiac Fibrosis: Key Roles of Smad7 and c-Ski. In: Srivastava, A.K., Anand-Srivastava, M.B. (eds) Signal Transduction in the Cardiovascular System in Health and Disease. Advances in Biochemistry in Health and Disease, vol 3. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-09552-3_13
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