Programmed cell death (apoptosis) is recognized, increasingly, as a contributing cause of cardiac myocyte loss with ischemia/reperfusion injury, myocardial infarction, and long-standing heart failure. While the molecular mechanisms initiating apoptosis in these settings remain unproven, it has been suggested that Bcl-2 family members including Bcl-2 itself and Bax are general regulators of apoptosis arising from the ceramide pathway, DNA damage, and other diverse causes. Using adenoviral gene transfer to cardiac myocytes in vitro, the Investigator has substantiated the predicted anti-apoptotic effect of Bcl-2 and adenoviral E1B (an inhibitor of Bax), in this cell background. Other established means to override apoptotic signals at least in cultured mammalian cells include: inhibitors of interleukin-1beta converting enzyme (ICE)/CED-3 family proteases; mutations of the cytokine receptor Fas/APO-1 and related """"""""death domain"""""""" proteins; the family of mammalian or baculovirus inhibitor of apoptosis proteins (IAPs); and a dominant-negative form of hepatic leukemia factor (HLF), a mammalian homologue for the transcription factor CES-2, a conserved cell death specification protein in Caenorhabditis elegans. At present, however, little or nothing is known concerning the potential to protect mammalian ventricular muscle from apoptosis, through one or more of these mechanisms. In the present proposal, methods recently developed for reproducible adenoviral gene transfer to adult mouse myocardium will be used to test the hypotheses that adenoviral delivery of: (1) Bcl-2 and BCl-xL, (2) ICE/CED-3 protease inhibitors, (3) dominant- interfering """"""""death domain"""""""" proteins, (4) IAPs, and (5) dominant- interfering CES-2 transcription factor: will be protective against cardiac apoptosis in vivo. Thus, this proposal will systematically test adenoviral gene transfer for protection from apoptosis after coronary artery ligation, for five complementary classes of protein with proven ability to inhibit apoptosis, at least in vitro. To date, only E1B and Bcl-2 are known to inhibit apoptosis of cardiac myocytes, even in culture. Given the extent of evidence for apoptosis as a cause of cardiac muscle death, especially in the acute settings of infarction and reperfusion injury, there is a compelling need for research that would define the molecular pathways driving apoptosis in these settings and for potential interventions to arrest the apoptotic pathway in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
1P50HL059314-01
Application #
6242852
Study Section
Project Start
1997-09-30
Project End
1998-08-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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