Date of Award

2014

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Eric R. Blough

Second Advisor

Todd Green

Third Advisor

Richard Egleton

Fourth Advisor

Nalini Santanam

Fifth Advisor

Elsa Mangiarua

Abstract

Despite continued advances in medical care, cardiovascular disease (CVD) remains the leading cause of death for American women [1]. Although humans and non-human primates are the only mammals to experience menses, rodent models are commonly used to study age-associated cardiovascular alterations due to similar ovarian aging, low expense, and short lifetime to investigate cardiovascular aging. Previous studies have found that aging in the female rodent is characterized by increased ventricular apoptosis, elevations in oxidative-nitrosative stress, ventricular remodeling, increased collagen content, mild systolic and diastolic dysfunction, and reduced occurrence of arrhythmias compared to males [2-7]. Similarly, age-associated alterations in the female rodent aorta have been shown to include increased proliferation/migration of vascular smooth muscle cells (VSMC) and endothelial dysfunction [8, 9]. However, no study has investigated the age-associated alterations in the female heart and aorta of the National Institute of Aging (NIA) approved Fischer 344/NNiaHSd x Brown Norway/BiNia (F344xBN) rat model. The NIA has recommended the F344xBN due to its longer maximal life span, higher age for 50% mortality, and the fact that it exhibits a normal distribution of age-related pathologies at later ages [10, 11]. Here, we investigated the effects of aging on cardiovascular structure and function in the adult, aged, and very aged female F344xBN rats. Compared to adult hearts, increased age was associated with increases in oxidative-nitrosative stress, oxidative damage, (increases in hydroethidine (HE) staining, 4-hydroxynonenal (4-HNE), and nitrotyrosine expression), and activation of the mitochondrial-mediated apoptosis pathway (increased number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive nuclei, increased activation of caspases, and Bax/Bcl-2 ratio). Age related changes in cardiac structure consisted of an increase in heart to body weight ratio, cardiomyocyte cross sectional area (CSA), posterior wall thickening, and left ventricle chamber dilatation. Coincident with these changes in cardiac structure and signaling, we also found that increased age was associated with evidence of diastolic dysfunction, alterations in heart rhythm intervals, and alterations in connexin 43 (Cx43) expression. The incidence of arrhythmias was not different with age; however, valvular dysfunction was increased. In the female F344xBN aorta there was an age-associated increase of intima-medial thickness and activation of p44/42 MAPK. Taken together, these results suggest that the female F344xBN rat may be an appropriate cardiovascular aging female rodent model in the absence of pathologies.

Subject(s)

Generative organs -- Aging

Aging -- Research

Aging - Animal models - Research

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