CARDIOCYTE RESPONSES TO HYPOXIA

  • Webster, Keith A, (PI)

Project: Research project

Description

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.
StatusFinished
Effective start/end date4/1/903/31/12

Funding

  • National Institutes of Health: $420,750.00
  • National Institutes of Health
  • National Institutes of Health: $336,056.00
  • National Institutes of Health: $294,508.00
  • National Institutes of Health: $382,500.00
  • National Institutes of Health
  • National Institutes of Health: $382,292.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $328,094.00
  • National Institutes of Health
  • National Institutes of Health: $367,364.00
  • National Institutes of Health: $382,500.00
  • National Institutes of Health
  • National Institutes of Health: $335,091.00
  • National Institutes of Health: $230,008.00
  • National Institutes of Health: $420,750.00
  • National Institutes of Health: $12,531.00
  • National Institutes of Health: $277,707.00
  • National Institutes of Health

Fingerprint

Cardiac Myocytes
Ischemia
Reperfusion
Apoptosis
Phosphotransferases
Oxidation-Reduction
Genes
Proteins
Infarction
Oxygen
Molecular Biology
Cell Death
Hypoxia
BH3 Interacting Domain Death Agonist Protein
bcl-Associated Death Protein
Myocardial Infarction
Myocardial Ischemia
Myoglobin
Apoptosis Regulatory Proteins
Phosphoproteins

ASJC

  • Medicine(all)