Angiotensin II (AngII) and its G protein-coupled AT1 receptor play critical roles in mediating cardiovascular diseases such as hypertension, atherosclerosis, and restenosis after vascular injury. It is widely believed that AngII promotes these diseases by inducing vascular remodeling that involves hypertrophy, proliferation, and migration of vascular smooth muscle cells (VSMCs). During our past funding period, we have shown that transactivation of an ErbB family receptor, EGF receptor (EGFR), is essential for VSMC hypertrophy and migration by AngII. Also, mature HB-EGF production/shedding through activation of a metalloprotease, ADAM17, appears to be an indispensable signaling event for the AngII-induced EGFR transactivation in VSMCs. Moreover, our past and preliminary results strongly suggest existence of Gq-derived 2nd messengers that are upstream of the ADAM17 activation via the AT1 receptor. However, the exact signal transduction mechanism(s) by which AngII promotes ADAM17 activation in VSMCs as well as its impact in mediating vascular remodeling in vivo remains unclear, and thus is essential for our research team to explore. Based on our past findings together with our recent preliminary results, we have built attractive hypotheses on the above- mentioned mechanism(s). Therefore, the specific aims of this renewal application are designed to explore the novel signal transduction concepts of the ADAM17 activation in VSMCs as well as to prove the functional and "translational" significance of the activation in vivo.
Aim 1. To test the hypothesis that tyrosine phosphorylation and subsequent interaction with newly-identified ADAM17 binding protein(s) are essential for ADAM17 activation by the AT1 receptor in VSMCs.
Aim 2. To test the hypothesis that the cholesterol-rich membrane micro-domains provide an indispensable environment for ADAM17 activation by AngII and the resultant shedding of HB-EGF.
Aim 3. To test the hypothesis that activation of ADAM17 in vascular smooth muscle by the above mechanism is the critical target of intervention for prevention of vascular remodeling in vivo. Our past substantial accomplishments together with accumulating preliminary results and the significant capabilities of our research team strongly warrant the feasibilities of the entire proposal. Successful accomplishment of these specific aims will not only provide us with the critical molecular mechanisms underlying vascular remodeling stimulated by AngII, but will also contribute to the development of novel treatment strategies toward cardiovascular diseases.

Public Health Relevance

This project was designed to identify novel signaling mechanisms regarding the function of angiotensin II in vascular cells, which will potentially help us to develop better treatments toward cardiovascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Tolunay, Eser
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Temple University
Schools of Medicine
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Takayanagi, Takehiko; Forrester, Steven J; Kawai, Tatsuo et al. (2016) Vascular ADAM17 as a Novel Therapeutic Target in Mediating Cardiovascular Hypertrophy and Perivascular Fibrosis Induced by Angiotensin II. Hypertension 68:949-55
Obama, Takashi; Takayanagi, Takehiko; Kobayashi, Tomonori et al. (2015) Vascular induction of a disintegrin and metalloprotease 17 by angiotensin II through hypoxia inducible factor 1α. Am J Hypertens 28:10-4
Takayanagi, Takehiko; Kawai, Tatsuo; Forrester, Steven J et al. (2015) Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II. Hypertension 65:1349-55
Obama, Takashi; Tsuji, Toshiyuki; Kobayashi, Tomonori et al. (2015) Epidermal growth factor receptor inhibitor protects against abdominal aortic aneurysm in a mouse model. Clin Sci (Lond) 128:559-65
Takayanagi, Takehiko; Crawford, Kevin J; Kobayashi, Tomonori et al. (2014) Caveolin 1 is critical for abdominal aortic aneurysm formation induced by angiotensin II and inhibition of lysyl oxidase. Clin Sci (Lond) 126:785-94
Obama, Takashi; Eguchi, Satoru (2014) Integrin-linked kinase: a new member of the kinases involved in hypertensive end-organ damage? Clin Sci (Lond) 127:15-7
Obama, Takashi; Eguchi, Satoru (2014) MicroRNA as a novel component of the tissue renin angiotensin system. J Mol Cell Cardiol 75:98-9
Obama, Takashi; Scalia, Rosario; Eguchi, Satoru (2014) Targeting neutrophil: new approach against hypertensive cardiac remodeling? Hypertension 63:1171-2
Elliott, Katherine J; Kimura, Keita; Eguchi, Satoru (2013) Lack of specificity of commercial antibodies leads to misidentification of angiotensin type-1 receptor protein. Hypertension 61:e31
Elliott, Katherine J; Bourne, Allison M; Takayanagi, Takehiko et al. (2013) ADAM17 silencing by adenovirus encoding miRNA-embedded siRNA revealed essential signal transduction by angiotensin II in vascular smooth muscle cells. J Mol Cell Cardiol 62:1-7

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