Targeting the transforming growth factor (TGF)-β cascade in the remodeling heart: benefits and perils.

Transforming Growth Factor (TGF)-β is a central regulator of cellular function in health and disease. Extensive evidence suggests that activation of TGF-β signaling cascades regulates cell survival, proliferation, migration and differentiation, and is critically implicated in tissue inflammation, repair, remodeling and fibrosis [1], [2], [3]. Most tissues contain large stores of latent TGF-β [4]; generation and release of active TGF-β following injury can modulate phenotype and function of all cell types involved in reparative, inflammatory and fibrotic responses. TGF-β signals by binding and sequentially transphosphorylating type II and type I receptors on the cell surface [5]. Seven type I receptors, also known as activin receptor like kinases (ALKs), and five type II receptors have been described. Most cellular effects of TGF-β are mediated through binding to ALK5 and subsequent activation of cascades that involve the intracellular effectors Smad2 and Smad3. In certain cell types (such as endothelial cells), TGF-β may also signal by activating ALK1, thus transducing Smad1 and Smad5 cascades [6]. Differential cell-specific activation of distinct type I receptors may explain the functional complexity of the pathophysiologic actions of the members of the TGF-β superfamily. Like most tissues, the heart contains a significant amount of latent TGF-β. Following cardiac injury, release of proteases, oxidative stress and induction of matricellular proteins cooperate to activate preformed stores of TGF-β, [7], while de novo synthesis of TGF-β isoforms contributes to accentuation of the response [8]. In the pressure-overloaded myocardium, release of bioactive TGF-β in the cardiac interstitium elicits responses in both cardiomyocytes and interstitial cells, critically regulating geometry and function of the remodeling ventricle [9]. TGF-β signaling cascades have been implicated in the pathogenesis of cardiac hypertrophy and interstitial fibrosis [9], [10], [11], suggesting that targeting the TGF-β system may hold promise in the treatment of heart failure [12], [13]. However, the pleiotropic, multifunctional and context-dependent actions of TGF-β signaling raise significant concerns regarding the outcome of interventions targeting TGF-β in patients with heart disease. The study by Engebretsen and co-workers [14] provides a highly informative illustration of the potential benefits and perils associated with manipulation of the TGF-β cascade in a clinically relevant rodent model of heart failure. The authors studied the effects of ALK5 inhibition in the pressure overloaded myocardium by treating mice undergoing transverse aortic constriction protocols with SM16, an orally active ALK5 inhibitor. ALK5 inhibition attenuated diastolic dysfunction, reducing fibrosis and decreasing deposition of cross-linked collagen in the cardiac interstitium. However, these beneficial effects came at a heavy cost: mice treated with SM16 had increased mortality (due to rupture of the ascending aorta), exhibited accentuated chamber dilation and developed inflammatory valve lesions. The findings highlight the risks of pharmacologic interventions targeting the TGF-β cascade in cardiac remodeling. Although blockade of TGF-β-induced fibrosis is an attractive therapeutic target for patients with heart failure, broad non-specific inhibition of TGF-β signaling in the remodeling myocardium may have catastrophic consequences. In order to understand the basis for these adverse events and to optimally design treatment strategies targeting TGF-β in patients with heart disease, we need to dissect the cell-specific effects of TGF-β cascades in the remodeling heart.