The expression of the HIV protein, Tat, has global effects on cell function including alterations in cytokine expression, transcription factors, and oxidative state of the cells. Most of these are important modulators of myocardial function and may exert potent effects particularly when the heart is stressed. The ability of the heart to respond to the increased demands requires use of metabolic reserve to supply high energy phosphates, and contractile reserve elicited by mobilizing calcium supplies for greater contractility and heart rate. In utilizing these reserves, mitochondrial function is enhanced, as is leakage of oxygen radicals. Loss of antioxidant capacity may compromise myocardial function during increased work and increased metabolic demand and especially during oxidative stress and increased cytokine production subsequent to endotoxin administration. The hypotheses to be tested in this proposal are three fold: 1) HIV-1 infection, as studied with a transgenic mouse model in which the Tat gene promoter is expressed and Tat protein is present in many tissues, causes loss of myocardial contractile reserve, i.e. impairs the response of the heart to physiologic stresses and leaves the heart more susceptible to injury from oxidative challenge and endotoxemia; 2) chronic alcohol consumption potentiates the detrimental effects of HIV (Tat expression) on myocardial function and reserve; and 3) treatment with the antiretroviral agent, AZT, potentiates the effects of Tat and alcohol on myocardial function and reserve. Alcohol and AZT treatment exacerbate Tat induced dysfunction by further upsetting the antioxidant balance in cells and promoting cytokine production. The function of the heart will be assessed with the isolated work performing heart and plasma and tissue cytokines and biochemical markers of myocardial oxidative injury and antioxidant capacity will be measured by standard techniques.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA013555-01A1
Application #
6573788
Study Section
Special Emphasis Panel (ZAA1-DD (22))
Program Officer
Bryant, Kendall
Project Start
2002-09-30
Project End
2005-08-31
Budget Start
2002-09-30
Budget End
2003-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$139,903
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Physiology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
McDonough, Kathleen H; Doumen, Chris; Giaimo, Mary et al. (2010) Effects of the HIV-1 protein Tat on myocardial function and response to endotoxin. Cardiovasc Toxicol 10:250-8