Tumor Necrosis Factor-α–Converting Enzyme Roles in Hypertension-Induced Hypertrophy

Abstract

In response to hypertension, the left ventricle (LV) initially responds with a concentric left ventricular hypertrophy, which compensates for the increase in pressure to normalize LV wall stress. After prolonged hypertension, however, the LV decompensates with increased fibrosis and dilation and can lead to heart failure.1 The LV response to pressure loading involves the intersection of multiple intracellular (myocytes, fibroblasts, and inflammatory cells) and extracellular matrix signaling pathways. Enzyme systems that degrade the extracellular matrix, namely, the matrix metalloproteinase (MMP), serine protease, and a disintegrin and metalloproteinase (ADAM) families, play key roles in regulating extracellular matrix turnover. In this issue of Hypertension , Wang et al2 examine the role of the tumor necrosis factor (TNF)-α–converting enzyme (TACE; also known as ADAM-17) in mediating cardiac hypertrophy and fibrosis. Using 2 models (the spontaneously hypertensive rat and a mouse model of angiotensin II infusion), they demonstrate that inhibition of TACE depresses pressure-overload–stimulated hypertrophic and fibrotic responses and concomitantly decreases MMP-2 and ADAM-12 levels without significantly lowering blood pressure. The ADAM family contains 21 functional transmembrane enzymes with a broad range of membrane protein substrates.3 MMP-2 substrates include collagen IV, transforming growth factor-β, insulin-like growth factor binding protein, and fibroblast growth factor receptor 14; ADAM-12 substrates include heparin binding-epidermal growth factor, type IV collagen, and fibronectin; and TACE substrates include TNF-α, TNF receptors I and II, interleukin 1 receptor II, transforming growth factor-α, heparin binding-epidermal growth factor, amphiregulin, and several G proteins.5 These 3 proteases have been shown previously …