The complex pattern of SMAD signaling in the cardiovascular system

The SMAD (small mother against decapentaplegic) family comprises transcription factors that function as signal transducers of TGF beta (transforming growth factor) superfamily members. The number of studies showing expression, activation or involvement of both SMAD and TGF beta family members in cardiovascular diseases is constantly rising. In this context, the position of SMADs in the diseased heart is particularly interesting because, besides their well-known fibrotic effects, increasing evidence demonstrates direct action of SMADs on cardiomyocytes as well as on the vascular system. In these systems, SMAD proteins are described to have effects on heart development, cell proliferation, cell growth, and apoptosis. As will be discussed in this review, these different consequences of SMAD activation are dependent on different SMAD isoforms, interaction of SMAD with other transcription factors in the particular situation, and modulation of SMAD activity by various kinases. As a result of all these influences, it turns out that activation of SMAD by members of the BMP (bone morphogenetic protein) family, which is a subfamily of the TGF beta superfamily, is necessary for correct heart development. On the other hand, activation of SMADs by TGF beta family members results in fibrotic, apoptotic, and anti-hypertrophic processes that are related to a detrimental cardiac remodeling and progression to heart failure. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.