Tumor Necrosis Factor-α–Converting Enzyme Roles in Hypertension-Induced Hypertrophy
Look Both Ways When Crossing the Street
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 to increase in human hypertrophic cardiomyopathy.6 Both MMP-2 and ADAM-12 have been shown to increase TGF-β activation, via increased Smad expression, which places these 2 proteases directly upstream of fibrosis.
In the first set of experiments, Wang et al2 used 22-week–old spontaneously hypertensive rats and treated 1 group with TACE small-interfering RNA for 2 weeks, followed by a 9-day no-treatment period and a final additional 2-week treatment period. At 22 weeks old, the spontaneously hypertensive rat typically shows hypertension and hypertrophy but no signs of heart failure compared with the Wistar-Kyoto control rat. At the end of the study, the untreated spontaneously hypertensive rat showed a further increase in LV mass:body weight ratios, whereas rats treated with TACE small-interfering RNA showed reduced LV:body weight ratios. TACE activity, MMP-2 levels, and phosphorylated extracellular signal–regulated kinase 1/2 levels were also lower in the treated group, all without a statistically significant (but may be biologically important) 20-mm Hg decrease in systolic blood pressure.
The authors also treated mice with angiotensin II for 10 to 12 days to induce hypertension. In the group pretreated with TACE small-interfering RNA, the mice showed increased blood pressure (above baseline values but with a mean below untreated values). Despite the increased blood pressure, the mice treated with TACE small-interfering RNA had decreased TACE levels, no appreciable LV hypertrophy or increase in myocyte cross-sectional areas, little evidence of fibrosis, and MMP-2 and ADAM-12 levels normalized toward baseline values.
Previous work has shown the following: (1) several ADAM members are increased in hypertrophy and heart failure6; (2) tissue inhibitor of metalloproteinase 3, the endogenous inhibitor of ADAM-12 and -17, is decreased in dilated cardiomyopathy7; and (3) several MMPs, including MMP-7, interact with ADAM family members.8 Wang et al2 extend these observations to show that TACE may be an upstream mediator of the hypertrophic response after pressure overload (Figure). A key concept underscored by this study is that, for ADAMs, as is true for MMPs and other protease systems, enzyme activation is hierarchical, with some family members acting upstream of others in the signaling pathway. MMP-3 is a well-known upstream activator of additional MMPs, and MMP-14 and tissue inhibitor of metalloproteinase 2 catalyze the activation of MMP-2.9 However, we still do not know the exact location in the cascade for each of these enzymes, eg, whether MMP-2 and ADAM-12 are in parallel or series to one another. It is possible that inhibiting 1 MMP or ADAM may disrupt an entire downstream network if the right enzyme is selected for inhibition and alternate or parallel networks are not influenced simultaneously.
The fact that blood pressure was not significantly lowered but hypertrophy at the whole organ and individual myocyte levels was blocked suggests that a long-term deleterious effect of TACE inhibition may be observed. Elevated blood pressure without a compensatory hypertrophic response would increase LV wall stress, which may predispose these ventricles to wall thinning and dilation. It is possible that TACE is increased in response to pressure overload as a means to protect, and this study highlights the need to mechanistically understand and extend observational studies to understand why a specific factor is expressed in response to hypertension. What compensation would occur in the long-term, in the absence of TACE levels and hypertrophy, is not known.
Another question that remains to be answered is how downstream signaling pathways activated or inactivated (directly or indirectly) by the downregulation of TACE are affected. In addition, MMPs, tissue inhibitor of metalloproteinases, and ADAMs are not the only regulators of extracellular matrix turnover. Serine proteases are another family of enzymes that need to be added into the equation.
How do the results presented by Wang et al2 potentially translate to the clinic? TACE inhibition by tumor necrosis factor-α protease inhibitor 2 does not change systolic blood pressure, but tumor necrosis factor-α protease inhibitor 2 also did not suppress TNF-α release in response to ex vivo cardiac global ischemia, underscoring the fact that we still do not have all of the details.10 Several inhibitors of the tumor necrosis factor-α pathway are currently available and are being tested in phase II clinical trials for rheumatoid arthritis. These include TMI-005 and BMS-561392. In addition, several TNF-α inhibitors, including Etanercept, Infliximab, and Adalimumab, are approved for the treatment of rheumatoid arthritis and other immune diseases, eg, Crohn’s disease and multiple sclerosis.11 It is interesting that increased infection rates are observed as an adverse effect of these agents. In terms of cardiac function, whether inflammatory pathways are inhibited, which would feed back to inhibit the fibrotic pathway, needs to be investigated. One would predict that, in the absence of cardiac stress, using a TACE inhibitor for rheumatoid arthritis would not pose a problem. However, in rheumatoid arthritis patients with hypertension or in patients with only hypertension, future evaluations on whether TACE inhibition serves a net benefit are warranted.
In summary, the study by Wang et al2 connects the results of several previously published works to highlight several roles for TACE in regulating the complex signaling cascade of LV hypertrophy. Future studies will need to delineate the full complement of TACE roles to determine whether TACE inhibition would result in a positive outcome in the setting of hypertension.
Sources of Funding
We acknowledge grant support from National Institutes of Health grant R01 HL75360, American Heart Association Grant-in-Aid 0855119F, and the Morrison Fund (all to M.L.L.), as well as National Institutes of Health grant T32 HL07446 (to R.Z.).
Dr Chilton has previously received money from or conducted work for Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Takeda, Merck Sharp & Dohme, Medtronics, and Boston Scientific. The other authors report no potential conflicts of interest.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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