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Degree

Master of Science (MS), Wright State University, Pharmacology and Toxicology, 2012.

Abstract

Activation of the renin angiotensin system (RAS) is a well-known driving force, governing the aggravation and progression of CVD and associated target organ damage. Angiotensin (Ang) converting enzyme 2 (ACE2), a new member within the RAS family, was first cloned from the ventricle of patient with heart failure. ACE2 was shown to be upregulated under pathological conditions. We hypothesize that loss of ACE2 negatively affects cardiac function and exacerbates hypertrophic cardiomyopathy and aortic remodeling in response to Ang II. Eight weeks old ACE2 knock out (KO) and wild type (WT) mice were infused with Ang II s.c. (1000 ng/kg/min for 4 weeks) using osmotic pumps. Blood pressure (radiotelemetry), cardiac function (echocardiography) and cardiac/aortic structural damage (histology) were examined. At baseline before Ang II, ACE2 KO displayed a normal phenotype for cardiac function and blood pressure. After 4 weeks of Ang II infusion, the mean arterial pressure (MAP) was increased (~40% in WT and ~33% in ACE2 KO) with no differences between groups. However, ACE2 KO responded differently to the increased MAP. Cardiac function analysis revealed severe myocardial dysfunction shown by the lowered EF% (31% vs. 13%) as well as FS% (30% vs 6%) in ACE2 KO vs WT, respectively. In addition, the cardiac dysfunction was associated with hypertrophic cardiomyopathy shown by the increased left ventricular wall thickness as well as heart weight/ body weight ratio. Moreover, collagen staining in the myocardium and aorta revealed higher collagen percentage in ACE2 KO which indicates cardiovascular remodeling. Furthermore, results showed enhanced oxidative stress in the myocardium and aorta of Ang II infused ACE2 KO compared to Ang II WT. In conclusion, ACE2 attenuates myocardial maladaptive hypertrophy and cardiovascular remodeling in response to long term Ang II stimulation.

Subject Headings

Pharmacology; Toxicology

Keywords

pharmacology; toxicology

Committee / Advisors

Mariana Morris, PhD (Committee Chair)
Mark Anstadt, MD, FACS (Committee Member)
Roberta Pohlman, PhD (Committee Member)
Terry Oroszi, MS (Other)
Andrew Hsu, PhD (Other)

Pages

83p.

Document number: wright1343838851
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=wright1343838851

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