A model system of chronic ischemia/hypoxia is proposed to study mechanical failure and subsequent adaptation of mammalian heart cell cultures. Conditions of limited oxygen supply have been established which initially cause mechanical failure of the cardiac myocyte but over extended exposures invoke an adaptive response which restores contractility. The time course of this biphasic response of the cardiocytes to hypoxia was five to seven days. Preliminary data has indicated that this hypoxia mediated cycle is accompanied by some dramatic changes in the transcriptional activity of certain genes in particular those involved in bioenergetic pathways and the oxygen transport protein myoglobin. Additional preliminary studies have suggested that hypoxia mediates significant reductions of intracellular cyclic AM-P and that this may contribute directly not only to the molecular genetic responses but also to contractile responses of the cardiocytes to chronic hypoxia. 'ne long term objectives of the proposed studies are to relate these and other metabolic and molecular genetic changes to the hypoxia contraction inhibition/adaptation cycle and to deter-mine whether there are cause and effect relationships between the parameters. Since certain glycolytic enzyme genes appear to be super-induced in the hypoxic cardiocytes an investigation of the mechanism of this induction is proposed along with analyses of regulatory signals which allow these genes to respond so dramatically in the cardiocyte. The precise molecular mechanism for ischemia/hypoxia mediated contractile failure of cardiac myocyte is sill not known. It is proposed that the in vitro model described here offers some unique advantages to investigate not only contractile failure but also how the cardiocytes can adapt to and ultimately overcome the hypoxic stress. Since oxygen deprivation appears to be the primary insult leading, to fatality in the ischemic heart it is anticipated that these studies will lead to a more precise understanding of the principal molecular events which culminate in ischemic heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL044578-03
Application #
3473056
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1990-04-01
Project End
1995-03-31
Budget Start
1992-04-29
Budget End
1993-03-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Sri International
Department
Type
DUNS #
City
Menlo Park
State
CA
Country
United States
Zip Code
94025
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