Deleting Vascular ADAM17 Sheds New Light on Hypertensive Cardiac Hypertrophy
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See related article, pp 949–955
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 …