Abstract

This project elucidates mechanisms of dilated cardiomyopathy (DCM) in AIDS. Cardiac infection with human immunodeficiency virus-1 (HIV-1), intramyocardial activity of HIV-1 proteins, and toxicity from antiretroviral agents each is postulated to cause AIDS DCM, Experiments in this proposal assess the individual impact of HIV-1 infection, HIV-1 proteins, and anti-AIDS therapeutics on the structure and function of the cardiac myocyte in AIDS DCM. Transgenic mice (TG) serve as key biological tools to explore mechanisms of AIDS DCM. Three TG strategies define 1) effects of targeted myocardial expression of HIV-1 using a replication-incompetent HIV-1 (NL4-3 gag/pol) driven by the cardiac specific alpha myosin heavy chain (alpha-MyHC) promoter; 2) effects of targeted cardiac specific expression of HIV-1 enzymes (e.t. protease) driven by the alpha-MyHC promoter; and 3) systemic events in AIDS DCM using a published TG that expresses replication defective NL4-3 gag/pol systemically. TGs treated with anti-HIV-1 chemotherapy help define structural and functional cardiovascular side effects contributing to AIDS DCM.
AIMS address scientific questions about AIDS DCM:
AIM 1 (PATHOLOGICAL): to define myocardial structural changes cellularly and subcellularly. Experiments localize and quantitate cardiac and HIV-1 mRNAs and proteins and cardiac mtDNA and mtRNA in TGs with AIDS DCM. Light microscopy, transmission electron microscopy (TEM), immuno-TEM and in situ hybridization localize HIV-1 gene products and pinpoint HIV-1 in cardiac myocyte subcellular compartments.
AIM 2 (PHYSIOLOGICAL): to define cardiac performance in AIDS DCM. Isolated cardiac myocytes and work performing heart preparations identify changes in contractility and relaxation in TGs with AIDS DCM. Expression of cardiac Ca transporter proteins and their mRNAs is analyzed in isolated cardiac myocytes.
AIM 3 (CELL/MOLECULAR BIOLOGICAL): to define cardiac mtDNA replication, mtRNA abundance, and mitochondrial polypeptide synthesis in AIDS DCM. Southern and Northern analysis respectively define mtDNA and mtRNA abundance in TG hearts. Biosynthetic labeling of polypeptides is determined in isolated mitochondria. Altered expression of mtRNA and mitochondrial proteins reflect altered energy genesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059798-05
Application #
6389829
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Program Officer
Wang, Lan-Hsiang
Project Start
1997-09-30
Project End
2005-06-30
Budget Start
2001-09-01
Budget End
2005-06-30
Support Year
5
Fiscal Year
2001
Total Cost
$367,000
Indirect Cost

  Institution

Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322

  Publications

Kushnir, Vitaly A; Lewis, William (2011) Human immunodeficiency virus/acquired immunodeficiency syndrome and infertility: emerging problems in the era of highly active antiretrovirals. Fertil Steril 96:546-53
Chakrabarti, Swarup K; Wen, Yeshao; Dobrian, Anca D et al. (2011) Evidence for activation of inflammatory lipoxygenase pathways in visceral adipose tissue of obese Zucker rats. Am J Physiol Endocrinol Metab 300:E175-87
Kohler, James J; Hosseini, Seyed H; Green, Elgin et al. (2011) Tenofovir renal proximal tubular toxicity is regulated by OAT1 and MRP4 transporters. Lab Invest 91:852-8
Kohler, James J; Hosseini, Seyed H; Green, Elgin et al. (2010) Absence of mitochondrial toxicity in hearts of transgenic mice treated with abacavir. Cardiovasc Toxicol 10:146-51
Kohler, James J; Hosseini, Seyed H; Cucoranu, Ioan et al. (2010) Transgenic cardiac-targeted overexpression of human thymidylate kinase. Lab Invest 90:383-90
Kohler, James J; Hosseini, Seyed H; Hoying-Brandt, Amy et al. (2009) Tenofovir renal toxicity targets mitochondria of renal proximal tubules. Lab Invest 89:513-9
Kohler, James J; Hosseini, Seyed H; Cucoranu, Ioan et al. (2009) Murine cardiac mtDNA: effects of transgenic manipulation of nucleoside phosphorylation. Lab Invest 89:122-30
Kohler, James J; Cucoranu, Ioan; Fields, Earl et al. (2009) Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy. Lab Invest 89:782-90
Kohler, James J; Hosseini, Seyed H; Lewis, William (2008) Mitochondrial DNA impairment in nucleoside reverse transcriptase inhibitor-associated cardiomyopathy. Chem Res Toxicol 21:990-6
Kohler, James J; Hosseini, Seyed H; Green, Elgin et al. (2008) Cardiac-targeted transgenic mutant mitochondrial enzymes: mtDNA defects, antiretroviral toxicity and cardiomyopathy. Cardiovasc Toxicol 8:57-69

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