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Permanent link (DOI): https://doi.org/10.7939/R3697036Q

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The Role of ACE2 and Apelin in Cardiac and Vascular Diseases Open Access

Descriptions

Other title
Subject/Keyword
Apelin
Cardiovascular
ACE2
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Wang, Wang
Supervisor and department
Oudit, Gavin (Medicine)
Examining committee member and department
Kassiri, Zameneh (Physiology)
O'Brien, Edward (Medicine)
Oudit, Gavin (Medicine)
Seubert, John (Pharmacology)
Lopaschuk, Gary (Pharmacology)
Department
Department of Physiology
Specialization

Date accepted
2015-12-17T14:35:17Z
Graduation date
2016-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Both ACE2 and apelin have been reported playing important roles in regulating cardiovascular structure and function. In this study, we used ACE2 or apelin gene knockout or knockdown mice to explore the roles of ACE2 or apelin in cardiovascular diseases. In particular, we created animal disease models of various cardiovascular remodeling or heart failure by exogenous Angiotensin II infusion or increasing the cardiac afterload or myocardial ischemia/infarction by surgeries. We also used ex vivo. disease models in isolated heart or vascular perfusion. Thereafter we performed cardiovascular morphological studies together with functional assays and signaling pathways studies. The results show that ACE2 is a protective factor against Ang II or transverse aortic constriction induced pathological remodeling by decreasing fibrosis, reactive oxygen species and direct degrading of Ang II. Apelin also shows beneficial effects in ischemic heart disease by promoting angiogenesis; apelin also counteracts Ang II by up-regulate ACE2 and mediates Ang II induced ACE2 up-regulation. In a separate group of studies, we confirmed that ACE2 degrades Apelin in vivo with significant functional changes. All these results added to the understanding of how ACE2 and apelin maintain the homeostasis of the cardiovascular system and the involvement in diseases conditions. Finally, we designed and tested apelin analogues; the results showing the potential of apelin, especially apelin analogues with C-terminal active and protected from ACE2 hydrolysis, as a new target for treating cardiovascular disease.
Language
English
DOI
doi:10.7939/R3697036Q
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Wang W, McKinnie SM, Patel VB, Haddad G, Wang Z, Zhabyeyev P, Das SK, Basu R, McLean B, Kandalam V, Penninger JM, Kassiri Z, Vederas JC, Murray AG and Oudit GY. Loss of Apelin exacerbates myocardial infarction adverse remodeling and ischemia-reperfusion injury: therapeutic potential of synthetic Apelin analogues. Journal of the American Heart Association. 2013;2:e000249.Wang W, Patel VB, Parajuli N, Fan D, Basu R, Wang Z, Ramprasath T, Kassiri Z, Penninger JM and Oudit GY. Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease. Journal of molecular medicine. 2014;92:847-58.Kazemi-Bajestani SM, Patel VB, Wang W and Oudit GY. Targeting the ACE2 and Apelin Pathways Are Novel Therapies for Heart Failure: Opportunities and Challenges. Cardiol Res Pract. 2012;2012:823193.Wang W, Bodiga S, Das SK, Lo J, Patel V and Oudit GY. Role of ACE2 in diastolic and systolic heart failure. Heart Fail Rev. 2012;17:683-91.

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