Alterations in the stability of lysosomal membranes and subsequent enzyme release are believed to account for cellular damage induced by myocardial ischemia. We have established that the female sex steroid estradiol increases lysosomal membrane stability in the rat heart and decreases the activities of two lysosomal proteinases. Estradiol also prevented the redistribution (release) of three lysosomal enzymes from the sedimentable to the nonsedimentable fractions of rat hearts subjected to total ischemia (global autolysis) in vitro. We propose to determine whether estradiol can alter lysosomal properties only in the heart muscle, in the vasculature or in the interstitial cells of the heart. Initially we will determine the effects of estradiol administration in vivo on lysosomal membrane stability and enzyme activities in aortas from male and female rats. We will establish methodology (centrifugal elutriation, density gradient centrifugation, etc.) to isolate subpopulations of cell types which comprise the rat heart. The mechanism(s) which underlie stimulation and inhibition of subpopulations in vitro using hearts from male and female rats which have been injected with estradiol in vivo. Effects of estradiol administration in vitro will also be assessed. Our working hypothesis is that lysosomal enzyme release and redistribution in heart cells subjected to ischemia is stimulated by lipoxygenase products and Ca influx and that estradiol may inhibit lysosomal enzyme redistribution and release by preventing Ca influx and stimulating formation of cyclooxygenase products (via activation of prostaglandin cyclooxygenase and prostacyclin synthase). We expect that an increased understanding of how sex steroids like estradiol can alter lysosomal properties in the heart will facilitate the design of agents to moderate myocardial ischemic damage.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL027860-06
Application #
3339371
Study Section
Cardiovascular Study Section (CVA)
Project Start
1981-02-01
Project End
1987-07-31
Budget Start
1986-02-01
Budget End
1987-07-31
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Wayne State University
Department
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202