Physiological Implications and Mechanisms of Estrogen Protection Associated With Myocardial Ischemia /Reperfusion Injury

This dissertation tested the general hypothesis that estrogen (E2) provides cardioprotection that increases survival following cardiac arrest and resuscitation (CA/R) by (1) altering expression of calcium buffer genes and proteins in cells, providing a better capacity to handle ischemia/reperfusion (I/R) injury (i.e., classical actions) and (2) activating a signaling network that confers reductions in cell death following I/R injury (i.e., non-classical actions). The effects of E2 on gene and protein expression were evaluated in whole heart homogenates from male, female, and ovariectomized female rats (OVX). Results indicated that (1) calbindin and parvalbumin are expressed in the adult rat heart (2) ovariectomy causes a loss of parvalbumin protein expression (3) these 'calcium buffer' genes do not show any clear, time dependent changes following CA/R. The effects of circulating plasma E2 on cardiac function following I/R injury were evaluated in isolated hearts from male, OVX, and OVX rats with chronic (14 day) E2 supplementation (OE2). Rats were administered vehicle (DMSO), estrogen receptor antagonist (ICI 182,780), or endothelial nitric oxide synthase (eNOS) antagonist (L-w-nitro-L-arginine (L-NNA)) at appropriate times prior to E2 (5 mug/kg) that was administered 30 min before removal of the heart for mounting in a modified Langendorff apparatus. After stabilization, hearts were normothermically arrested for 20 min then reperfused for 60 min. Results demonstrated that 1) acute E2 administration preserved left ventricular (LV) contractility (dP/dtmax) and relaxation properties (dP/dtmin) in all groups 2) administration of L-NNA or ICI 182,780 prior to E2 blocked protection. Results indicated that circulating E2 protects from I/R injury in a sex-independent, ER/eNOS-dependent manner. The effects of chronic (14 day) E2 replacement were evaluated in a rat model of CA/R. Resuscitation rates, survival rates, and cell death were quantified following 4 min CA/R and 0-72 h of reperfusion. Results demonstrated that compared to male and OVX rats, OE2 exhibit (1) increased resuscitation and survival rates (2) absence of DNA laddering. In all, these results suggest that E2 provides cardioprotection from I/R injury in a physiologically relevant manner by utilizing both classical and non-classical mechanisms to increase survival following CA/R.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2005

Author dc:creator

• Stark, Jamie T.

Contributors dc:contributor

• David R. Gross

• Biology, Animal Physiology

Language dc:language

eng

Identifier

(MiAaPQ)AAI3202172

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/85359