Abdominal aortic aneurysm (AAA) is a significant cause of mortality for adults aged >60 years. No established pharmacological treatment is currently available to prevent AAA advancement and/or rupture. Accumulating evidence suggests critical roles for the renin angiotensin aldosterone system (RAAS) in AAA formation. While several downstream signals and target proteins of AT1 receptor have been identified, there is a huge void in our knowledge regarding the proximal signaling events primarily responsible for AAA. Unfortunately, efficacies of the AngII blockers for human AAA appear to be limited. It is likely that the critical AAA promoting signal inducible upon AT1 stimulation is shard by many other AAA-promoting risk factors, such as by aldosterone (Aldo), indicating that an AngII blocker alone is insufficient as a treatment. Thus, we propose to determine alternative therapeutic targets for AAA in the AngII signal transduction pathway shared with other risk factors. We recently reported that caveolae membrane microdomains in vascular smooth muscle cells (VSMC) mediate a metalloprotease ADAM17-dependent EGFR transactivation, which is linked to vascular remodeling induced by AngII. Our preliminary data showed complete failure of AngII to induce AAA in mice lacking VSMC ADAM17 suggesting that ADAM17 is a potential target to prevent AAA. EGFR activation, ER stress and oxidative stress associated with AAA formation were also attenuated in VSMC ADAM17 deficient mice. Moreover, loss or inhibition of ADAM17 associated signaling elements (knockout of the caveolae structural protein, caveolin-1 or treatment with EGFR inhibitor) prevented AngII-dependent AAA as well as ER/oxidative stress. Enhanced ADAM17 expression and EGFR activation were also confirmed in human AAA. While EGFR transactivation appears critical for Aldo/mineralocorticoid receptor (MR) signal transduction in VSMC, whether the VSMC caveolae ADAM17/EGFR axis is critical for Aldo-mediated AAA is unclear. Here, we have developed the following 2 Aims to answer our key hypotheses.
Aim 1. To investigate the contribution and mechanism of VSMC ADAM17 and EGFR in AAA. Hypothesis: VSMC ADAM17 is essential for AAA development and/or rupture through induction of ER stress and subsequent AAA associated genes/proteins via the novel feed forward loop of ADAM17/EGFR activation.
Aim 2. To investigate the VSMC Cav1 mechanism and its consequence for the mouse models of AAA. Hypothesis: VSMC Cav1 silencing prevents ER stress and subsequent AAA formation and/or rupture through prevention of vascular ADAM17 activation by BMX. To accomplish these 2 Aims, 3 different AAA models will be used with mice lacking VSMC ADAM17, EGFR or Cav1. For an AngII- or Aldo-dependent AAA model, the mice will be infused with AngII plus BAPN, a lysyl oxidase inhibitor or treated with DOCA salt plus BAPN, respectively. For a RAAS-independent AAA model, the mouse abdominal aorta will be treated with CaCl2 plus PBS. In addition, this RAAS-independent AAA model and cultured VSMC will be used together with adenovirus encoding miRNA-embedded siRNA targeting ADAM17, EGFR, Cav1 or BMX. Accomplishment of this proposal will explore the novel feed-forward loop mechanism initiated by vascular caveolae compartmentalized signaling molecules as a potential therapeutic target for reducing AAA development.

Public Health Relevance

This project was designed to identify new signaling mechanisms of membrane associated proteins, ADAM17, EGFR and BMX, in vascular cells using cell culture and model animals, which will potentially help us to develop better treatments toward cardiovascular diseases such as aortic aneurysm.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128324-02
Application #
9100916
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Tolunay, Eser
Project Start
2015-07-01
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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Cooper, Hannah A; Scalia, Rosario; Rizzo, Victor et al. (2018) Angiotensin II- and Alzheimer-Type Cardiovascular Aging. Circ Res 123:651-653
Forrester, Steven J; Booz, George W; Sigmund, Curt D et al. (2018) Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol Rev 98:1627-1738
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
Forrester, Steven J; Elliott, Katherine J; Kawai, Tatsuo et al. (2017) Caveolin-1 Deletion Prevents Hypertensive Vascular Remodeling Induced by Angiotensin II. Hypertension 69:79-86
Forrester, Steven J; Kawai, Tatsuo; O'Brien, Shannon et al. (2016) Epidermal Growth Factor Receptor Transactivation: Mechanisms, Pathophysiology, and Potential Therapies in the Cardiovascular System. Annu Rev Pharmacol Toxicol 56:627-53
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
Li, Xinyuan; Fang, Pu; Li, Yafeng et al. (2016) Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation. Arterioscler Thromb Vasc Biol 36:1090-100
Cannavo, Alessandro; Liccardo, Daniela; Eguchi, Akito et al. (2016) Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases. Nat Commun 7:10877

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