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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 (myocyte, fibroblasts, and inflammatory cells) and extracellular matrix signaling pathways. Enzyme systems that degrade extracellular matrix (ECM), namely the matrix metalloproteinase (MMP), serine protease, and a disintegrin and metalloproteinase (ADAM) families, play key roles in regulating ECM turnover. In this issue of Hypertension, Wang and colleagues examine the role of the TNFα converting enzyme (TACE, also known as ADAM-17) in mediating cardiac hypertrophy and fibrosis.2 Using two models (the spontaneously hypertensive rat (SHR) and a mouse model of angiotensin (Ang) 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 1;4 ADAM-12 substrates include heparin binding-epidermal growth factor (HB-EGF), type IV collagen, and fibronectin; and TACE substrates include TNFα, TNF receptors I and II, interleukin-1 receptor II, transforming growth factor α, HB-EGF, amphiregulin, and several G proteins.5 These three proteases have previously been shown to increase in human hypertrophic cardiomyopathy.6 Both MMP-2 and ADAM-12 have been shown to increase TGFβ activation, via increased SMAD expression, which places these two proteases directly upstream of fibrosis.
In the first set of experiments, Wang and colleagues used 22 week old SHR and treated one group with TACE siRNA for 2 weeks, followed by a 9 day no treatment period, and a final additional 2 week treatment period. At 22 weeks old, the SHR typically shows hypertension and hypertrophy but no signs of heart failure compared to the Wistar-Kyoto control rat. At the end of the study, the untreated SHR showed a further increase in LV mass to body weight ratios, while rats treated with TACE siRNA showed reduced LV to BW ratios. TACE activity, MMP-2 levels, and phosphorylated ERK ½ levels were also lower in the treated group—all without a statistically significant (but may be biologically important 20 mmHg decrease) in systolic blood pressure.
The authors also treated mice with Ang II for 10-12 days to induce hypertension. In the group pre-treated with TACE siRNA, 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 siRNA 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 towards baseline values.
Previous work has shown that i) several ADAM members are increased in hypertrophy and heart failure;6 ii) TIMP-3, the endogenous inhibitor of ADAM-12 and -17, is decreased in dilated cardiomyopathy;7 and iii) several MMPs, including MMP-7, interact with ADAM family members.8 Wang et al extend these observations to show that TACE may be an upstream mediator of the hypertrophic response following 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 TIMP-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, e.g., if MMP-2 and ADAM-12 are in parallel or series to one another. It is possible that inhibiting one MMP or ADAM may disrupt an entire downstream network, if the right enzyme is selected for inhibition and alternate or parallel networks are not simultaneously influenced.
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, TIMPs, and ADAMs are not the only regulators of ECM turnover. Serine proteases are another family of enzymes that need to be added into the equation.
How do the results presented by Wang et al potentially translate to the clinic? TACE inhibition by tumor necrosis factor α protease inhibitor-2 (TAPI-2) does not change systolic blood pressure, but TAPI-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. Additionally, several TNFα inhibitors, including Etanercept, Infliximab, and Adalimumab, are approved for the treatment of rheumatoid arthritis and other immune diseases such as Crohn's disease and multiple sclerosis.11 It is interesting that increased infection rates are observed as a side effect of these agents. In terms of cardiac function, whether inflammatory pathways are inhibited, which would feed back to inhibit the fibrotic pathway, need 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 al 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, in order to determine if TACE inhibition would result in a positive outcome in the setting of hypertension.
Sources of Funding: The authors acknowledge grant support from NIH R01 HL75360, AHA Grant-in-Aid 0855119F, and Morrison Fund to MLL, and T32 HL07446 to RZ.