Angiotensin II (Angll) 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 Angll promotes these diseases by inducing vascular remodeling that involves hypertrophy, hyperplasia, and migration of vascular smooth muscle cells (VSMCs). It has been shown that transactivation of an ErbB family receptor, EGF receptor (ErbB1/EGFR), is essential for VSMC hypertrophy and migration by Angll. However, the precise signal transduction mechanism by which Angll transactivates EGFR/ErbB1 and whether other ErbBs are also required for Angll function remains unclear. Recent studies suggest an involvement of a metalloprotease-dependent ErbB family ligand production in the transactivation. Thus, our central hypothesis is that an AT1-derived second messenger promotes activation of ADAM metalloprotease leading to ErbB receptors transactivation and subsequent remodeling in VSMCs. Our past and current preliminary studies strongly support our central hypothesis. Therefore, the specific aims of this application are designed to identify the signaling mechanism(s) and functional significance of the metalloprotease/ErbB activation by Angll in VSMCs.
The specific aims of the study are:
Aim 1. To test the hypothesis that G protein and second messengers are involved in metalloprotease activation through the AT1 receptor.
Aim 2. To test the hypothesis that ADAM metalloprotease is activated by a mechanism involving ADAM cytoplasmic tail and a cytosolic tyrosine kinase.
Aim 3. To test the hypothesis that several ErbB ligands are produced by Angll and mediate Angll-induced transactivation of ErbB receptors.
Aim 4. To test the hypothesis that the transactivation of ErbB receptors is required for hypertrophy and migration of VSMCs induced by Angll. Accomplishment of these specific aims will not only give us a better understanding of the critical molecular mechanism underlying vascular remodeling stimulated by Angll but will also contribute to development of novel treatment strategies toward cardiovascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Lin, Michael
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Temple University
Schools of Medicine
United States
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Kawai, Tatsuo; Takayanagi, Takehiko; Forrester, Steven J et al. (2017) Vascular ADAM17 (a Disintegrin and Metalloproteinase Domain 17) Is Required for Angiotensin II/?-Aminopropionitrile-Induced Abdominal Aortic Aneurysm. Hypertension 70:959-963
Kawai, Tatsuo; Forrester, Steven J; O'Brien, Shannon et al. (2017) AT1 receptor signaling pathways in the cardiovascular system. Pharmacol Res 125:4-13
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 68:949-955
Obama, Takashi; Takayanagi, Takehiko; Kobayashi, Tomonori et al. (2015) Vascular induction of a disintegrin and metalloprotease 17 by angiotensin II through hypoxia inducible factor 1?. Am J Hypertens 28:10-4
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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
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; Scalia, Rosario; Eguchi, Satoru (2014) Targeting neutrophil: new approach against hypertensive cardiac remodeling? Hypertension 63:1171-2
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

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