title: Vascular ADAM17 as a Novel Therapeutic Target in Mediating Cardiovascular Hypertrophy and Perivascular Fibrosis Induced by Angiotensin II.
abstract: Angiotensin II (AngII) has been strongly implicated in hypertension and its complications. Evidence suggests the mechanisms by which AngII elevates blood pressure and enhances cardiovascular remodeling and damage may be distinct. However, the signal transduction cascade by which AngII specifically initiates cardiovascular remodeling, such as hypertrophy and fibrosis, remains insufficiently understood. In vascular smooth muscle cells, a metalloproteinase ADAM17 mediates epidermal growth factor receptor transactivation, which may be responsible for cardiovascular remodeling but not hypertension induced by AngII. Thus, the objective of this study was to test the hypothesis that activation of vascular ADAM17 is indispensable for vascular remodeling but not for hypertension induced by AngII. Vascular ADAM17-deficient mice and control mice were infused with AngII for 2 weeks. Control mice infused with AngII showed cardiac hypertrophy, vascular medial hypertrophy, and perivascular fibrosis. These phenotypes were prevented in vascular ADAM17-deficient mice independent of blood pressure alteration. AngII infusion enhanced ADAM17 expression, epidermal growth factor receptor activation, and endoplasmic reticulum stress in the vasculature, which were diminished in ADAM17-deficient mice. Treatment with a human cross-reactive ADAM17 inhibitory antibody also prevented cardiovascular remodeling and endoplasmic reticulum stress but not hypertension in C57Bl/6 mice infused with AngII. In vitro data further supported these findings. In conclusion, vascular ADAM17 mediates AngII-induced cardiovascular remodeling via epidermal growth factor receptor activation independent of blood pressure regulation. ADAM17 seems to be a unique therapeutic target for the prevention of hypertensive complications.
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Takehiko
authors.initials: T
authors.lastname: Takayanagi
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Forrester
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Takashi
authors.initials: T
authors.lastname: Obama
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Elliott
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Hang Fai
authors.initials: HF
authors.lastname: Kwok
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Rosario
authors.initials: R
authors.lastname: Scalia
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Victor
authors.initials: V
authors.lastname: Rizzo
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA (T.T., S.J.F., T.K., T.O., T.T., Y.F., K.J.E., R.S., V.R., S.E.), Department of Pharmacy, University of Pisa, Pisa, Italy (E.N., A.R.), and Faculty of Health Sciences, University of Macau, Macau, China (HF.K.).
authors.forename: Satoru
authors.initials: S
authors.lastname: Eguchi
mesh_terms: D000072198:ADAM17 Protein / Q000187:drug effects* / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000517:prevention & control; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D032383:Myocytes, Cardiac / Q000378:metabolism; D011897:Random Allocation; D012084:Renin-Angiotensin System / Q000502:physiology; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D066253:Vascular Remodeling / Q000187:drug effects / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
chemical_list: D000804:Angiotensin II; D066246:ErbB Receptors; D000072198:ADAM17 Protein
keywords: end-organ damage; fibrosis; hypertension; renin angiotensin system; signal transduction