Deleting Vascular ADAM17 Sheds New Light on Hypertensive Cardiac Hypertrophy

Abstract

A disintegrin and metalloprotease (ADAM) 17 has sheddase activity for cleaving the ectodomain of several precursor molecules, including heparin-binding epidermal growth factor (EGF)-like growth factor. Over the past decade, Dr Eguchi and his colleagues have meticulously presented evidence that ADAM17 couples the angiotensin II (Ang II) type-1 (AT1) receptor to activation of the EGF receptor (EGFR) in vascular smooth muscle cells. Studies on cultured cells have shown that EGFR transactivation is responsible for vascular smooth muscle cell hypertrophy in response to Ang II, but not contractility. Moreover, EGF was found to be capable of inducing endoplasmic reticulum stress, which serves to enhance the coupling of Ang II to EGFR signaling by upregulating the expression of ADAM17. In a study that appeared last year in Hypertension, Eguchi's group reported that inhibiting EGFR or endoplasmic reticulum stress attenuated vascular remodeling and cardiac hypertrophy in mice infused with Ang II, without affecting the increase in blood pressure. 1 In the current issue, these investigators extend these observations further by showing that knockout of ADAM17 specifically in vascular smooth muscle cells prevents cardiac hypertrophy, vascular medial hypertrophy, and perivascular fibrosis in mice treated with Ang II, again without affecting the induced hypertension.2 ADAM17 deficiency also diminished EGFR activation and endoplasmic reticulum stress in the vasculature, and a similar outcome was achieved by treatment of Ang II-infused mice with a human cross-reactive ADAM17 inhibitory antibody ( Figure).These new findings are remarkable for several reasons. First, they provide additional support for the contention that increased blood pressure and adverse cardiovascular remodeling, which contributes to end-organ damage, are independent phenomena that can be targeted separately. This conclusion has profound clinical significance given that hypertension for many individuals is difficult to control with current drugs and strategies. Moreover, as mentioned by Takayanagi et al, 2 optimally treated hypertensive patients are at an increased risk of a cardiovascular event compared with untreated normotensive subjects. Thus, there is a great need to identify druggable targets to prevent the complications of hypertension, and ADAM17 may represent such a target.Left ventricular hypertrophy represents a stronger risk factor than increased blood pressure for adverse cardiovascular events, and accumulating evidence indicates that elevated blood pressure and cardiac hypertrophy can be targeted independently. Odenbach et al 3 reported evidence that it is possible to block hypertension and still observe cardiac hypertrophy and fibrosis in the Ang II-infused mouse by targeting matrix metalloproteinase 2 (MMP-2), which was placed downstream of MMP-7 and ADAM17 activation. MMP-7 and ADAM17 were linked to both hypertension and cardiac remodeling by independent mechanisms. Simultaneously knocking down MMP-7 and ADAM17 with siRNA attenuated both Ang I...

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…Of course, issues such as genetic compensation with germline gene KO, potential experimental immunosuppression or preconditioning with renal transplants, and the sheer magnitude of the stress on the heart with pressure overload, could be raised to question the broad applicability of these findings. Several recent studies support the conclusion that ANG II can act independently of, or in synergy with, increased blood pressure to induce cardiac hypertrophy (27,523). Three examples are cited here.…”

“…Investigation of this model has contributed to our understanding of the relationship between the RAS, oxidative stress, and perivascular fibrosis. In young mRen2 (27) rats, an antioxidant, Tempol, prevents cardiac oxidative stress and perivascular fibrosis without altering hypertension (1144). A subsequent study also showed that low-dose MR blocker, spironolactone, attenuates perivascular fibrosis and cardiac NADPH oxidase activity, suggesting the contribution of MR activation in this model (350).…”

“…The transgenic mRen2 (27) rat is a unique model of enhanced RAS activity in which tissue renin, ANG II, and circulating aldosterone are increased leading to hypertensive cardiovascular remodeling and inflammation. Investigation of this model has contributed to our understanding of the relationship between the RAS, oxidative stress, and perivascular fibrosis.…”

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“…28 Thus, smooth muscle AT1 receptor function may regulate cardiac hypertrophy by intercellular signaling and paracrine factors involving the vasculature. 29…”