TGF-h1 and angiotensin networking in cardiac remodeling

The renin–angiotensin system (RAS) and transforming growth factor-h1 (TGF-h1) play a pivotal role in the development of cardiac hypertrophy and heart failure. Recent studies indicate that angiotensin II (Ang II) and TGF-h1 do not act independently from one another but rather act as part of a signalling network in order to promote cardiac remodeling, which is a key determinant of clinical outcome in heart disease. This review focuses on recent advances in the understanding, how Ang II and TGF-h1 are connected in the pathogenesis of cardiac hypertrophy and dysfunction. Increasing evidence suggests that at least some of the Ang II-induced effects on cardiac structure are mediated via indirect actions. Ang II upregulates TGF-h1 expression via activation of the angiotensin type 1 (AT1) receptor in cardiac myocytes and fibroblasts, and induction of this cytokine is absolutely required for Ang II-induced cardiac hypertrophy in vivo. TGF-h induces the proliferation of cardiac fibroblasts and their phenotypic conversion to myofibroblasts, the deposition of extracellular matrix (ECM) proteins such as collagen, fibronectin, and proteoglycans, and hypertrophic growth of cardiomyocytes, and thereby mediates Ang II-induced structural remodeling of the ventricular wall in an auto-/paracrine manner. Downstream mediators of cardiac Ang II/TGF-h1 networking include Smad proteins, TGFh-activated kinase-1 (TAK1), and induction of hypertrophic responsiveness to h-adrenergic stimulation in cardiac myocytes. D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. lv ania State U niersity