Title

Vascular ADAM17 (a Disintegrin and Metalloproteinase Domain 17) Is Required for Angiotensin II/β-Aminopropionitrile-Induced Abdominal Aortic Aneurysm

Authors

Tatsuo Kawai, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Takehiko Takayanagi, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Steven J. Forrester, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Kyle J. Preston, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Takashi Obama, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Toshiyuki Tsuji, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Tomonori Kobayashi, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Michael J. Boyer, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Hannah A. Cooper, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Hang Fai Kwok, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Tomoki Hashimoto, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Rosario Scalia, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.).
Victor Rizzo, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.). seguchi@temple.edu rizzov@temple.edu.
Satoru Eguchi, From the Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (T. Kawai, T. Takayanagi, S.J.F., K.J.P., T.O., T. Tsuji, T. Kobayashi, M.J.B., H.A.C., R.S., V.R., S.E.); Faculty of Health Sciences, Macau Special Administrative Region, University of Macau, Taipa (H.F.K.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco (T.H.). seguchi@temple.edu rizzov@temple.edu.

Document Type

Article

Abstract

Angiotensin II (AngII)-activated epidermal growth factor receptor has been implicated in abdominal aortic aneurysm (AAA) development. In vascular smooth muscle cells (VSMCs), AngII activates epidermal growth factor receptor via a metalloproteinase, ADAM17 (a disintegrin and metalloproteinase domain 17). We hypothesized that AngII-dependent AAA development would be prevented in mice lacking ADAM17 in VSMCs. To test this concept, control and VSMC ADAM17-deficient mice were cotreated with AngII and a lysyl oxidase inhibitor, β-aminopropionitrile, to induce AAA. We found that 52.4% of control mice did not survive because of aortic rupture. All other surviving control mice developed AAA and demonstrated enhanced expression of ADAM17 in the AAA lesions. In contrast, all AngII and β-aminopropionitrile-treated VSMC ADAM17-deficient mice survived and showed reduction in external/internal diameters (51%/28%, respectively). VSMC ADAM17 deficiency was associated with lack of epidermal growth factor receptor activation, interleukin-6 induction, endoplasmic reticulum/oxidative stress, and matrix deposition in the abdominal aorta of treated mice. However, both VSMC ADAM17-deficient and control mice treated with AngII and β-aminopropionitrile developed comparable levels of hypertension. Treatment of C57Bl/6 mice with an ADAM17 inhibitory antibody but not with control IgG also prevented AAA development. In conclusion, VSMC ADAM17 silencing or systemic ADAM17 inhibition seems to protect mice from AAA formation. The mechanism seems to involve suppression of epidermal growth factor receptor activation.

Keywords

aneurysm, angiotensin II, hypertension, rupture, signal transduction

Medical Subject Headings

ADAM17 Protein (antagonists & inhibitors, metabolism); Aminopropionitrile (metabolism); Angiotensin II (metabolism); Animals; Aorta, Abdominal (metabolism, pathology); Aortic Aneurysm, Abdominal (etiology, metabolism, pathology, prevention & control); ErbB Receptors (metabolism); Hypertension (etiology, metabolism, prevention & control); Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular (metabolism, pathology); Protein-Lysine 6-Oxidase (metabolism); Receptor Activity-Modifying Proteins (metabolism); Signal Transduction (physiology)

Publication Date

11-1-2017

Publication Title

Hypertension (Dallas, Tex. : 1979)

E-ISSN

1524-4563

Volume

70

Issue

5

First Page

959

Last Page

963

PubMed ID

28947615

Digital Object Identifier (DOI)

10.1161/HYPERTENSIONAHA.117.09822

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