Date of Award

2011

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

Elsa I. Mangiarua

Fourth Advisor

Nalini Santanam

Fifth Advisor

Robert Harris

Abstract

Despite advances in therapeutic and diagnostic strategies cardiovascular disease still remains the leading cause of death in older people. Recent studies suggest that age- related elevations in oxidative stress are associated with increases in cardiac apoptosis and compensatory hypertrophy of the remaining cardiomyocytes. Acetaminophen has been shown to exhibit cardioprotective effects following ischemia-reperfusion injury by acting as an antioxidant. Here, we investigate the molecular mechanisms underlying aging associated cardiac remodeling in male F344XBN rats and examine the efficacy of chronic acetaminophen ingestion as a therapeutic approach.

Aging in male F344XBN rats is characterized by a significant increase in heart size, heart weight, heart weight to body weight ratio and cardiomyocytes fiber cross sectional area. Our findings suggest that aging-associated cardiac hypertrophy in F344XBN rats is predominantly mediated via activation of the extracellular regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) signaling pathways resulting in increased protein translational signaling and ultimately increased protein synthesis.

To determine the efficacy of chronic acetaminophen treatment in preventing age- related alterations in cardiac structure and function, male F344XBN rats (27-mo; n=6) were treated with acetaminophen (30mg/kg/day p.o.) for six months and underwent serial electrocardiography before and after the completion of the study. Compared to 6-month and 33-month age matched control rats, chronic acetaminophen ingestion diminished age-related increases in cardiac ROS levels and the number of TUNEL positive nuclei. These changes were accompanied by improvements in the Bax/Bcl2 ratio, diminished evidence of caspase-3 activation and increased phosphorylation of Akt, ERK1/2, p70S6K and GSK-3β. In addition, acetaminophen treatment diminished age-related increases in the incidence of arrhythmias and these alterations were associated with diminished fibrosis and changes in cardiac miRNA expression. Taken together, these results suggest that acetaminophen may attenuate the age associated deterioration in cardiac structure and function possibly via diminishing age associated elevation in reactive oxygen species production.

Subject(s)

Heart - Hypertrophy - Age factors.

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