Background: Myocardial inflammation with pericardial effusions leading to cardiac tamponade and cardiomyopathies are a frequent finding in AIDS patients. Up-regulation of microvascular endothelial cell adhesion molecule (CAM) expression by oxidants and/or circulating cytokines produces a hyperadhesive endothelium that preferentially sequesters leukocytes and contributes to the inflammatory process. Further secretion of oxidants, pro-inflammatory mediators and/or proteases by these cells causes alterations to the endothelial permeability barrier, setting up a cascade of events that end in cardiomyocyte dysfunction and cardiac failure. The cardiac pathologies in AIDS patients occur even in the absence of known opportunistic infections or direct infection by HIV, suggesting the existence of a soluble factor, either of viral of cellular origin. This soluble factor may be the HIV-1 Tat protein. It is proposed that release of the soluble HIV-1 Tat regulatory protein from infected cells and its uptake by uninfected cells increases oxidant stress, affects NF-kB activation and elevates CAM levels, which sequesters leukocytes and depresses cardiac cell function. The mechanisms underlying this process relates to inhibition of the target cell's antioxidant enzymes Mn-SOD and is reflected by a perturbed GSH/GSSG ratio. Therefore, the specific aims are to test the hypotheses that 1) Tat-dependent Mn-SOD inhibition of cardiac microvascular endothelial cells increases oxidant stress 2) that Tat-mediated oxidants stress results in CAM up-regulation, possibly via NF-kB and/or AP-1 activation 3) that Tat increases cytokine secretion 4) that these Tat-mediated alterations increase leukocyte-endothelial cell interactions 5) that Tat also mediates increases in vascular permeability. All of these events converge to affect the integrity of cardiac endothelium and may therefore result in some of the cardiovascular abnormalities seen in AIDS. The effect of Tat on cardiac endothelial cell, and/or leukocyte function will be evaluated in cells isolated from human sources and from Tat-transgenic mice. The proposed research addresses one of the important questions regarding the etiology of cardiovascular complications in AIDS: why is there evidence of myocarditis, yet very little evidence of a pathogenic viral, bacterial, or fungal agent? Tat-mediated oxidative stress may be an important contributor to the cardiac inflammation seen in these patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL059785-01
Application #
2539908
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Project Start
1997-09-01
Project End
2002-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Almodovar, Sharilyn; Swanson, Jessica; Giavedoni, Luis D et al. (2018) Lung Vascular Remodeling, Cardiac Hypertrophy, and Inflammatory Cytokines in SHIVnef-Infected Macaques. Viral Immunol 31:206-222
Honda, Jennifer R; Hess, Tamara; Malcolm, Kenneth C et al. (2015) Pathogenic nontuberculous mycobacteria resist and inactivate cathelicidin: implication of a novel role for polar mycobacterial lipids. PLoS One 10:e0126994
Honda, Jennifer R; Shang, Shaobin; Shanley, Crystal A et al. (2011) Immune Responses of HIV-1 Tat Transgenic Mice to Mycobacterium Tuberculosis W-Beijing SA161. Open AIDS J 5:86-95
Cota-Gomez, Adela; Flores, Ariana C; Ling, Xiao-Feng et al. (2011) HIV-1 Tat increases oxidant burden in the lungs of transgenic mice. Free Radic Biol Med 51:1697-707
Marecki, John C; Cool, Carlyne D; Parr, Jane E et al. (2006) HIV-1 Nef is associated with complex pulmonary vascular lesions in SHIV-nef-infected macaques. Am J Respir Crit Care Med 174:437-45
Ling, Xiaofeng; Cota-Gomez, Adela; Flores, Natalia C et al. (2005) Alterations in redox homeostasis and prostaglandins impair endothelial-dependent vasodilation in euglycemic autoimmune nonobese diabetic mice. Free Radic Biol Med 39:1089-98
Tuder, Rubin M; Zhen, Lijie; Cho, Chung Y et al. (2003) Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am J Respir Cell Mol Biol 29:88-97
Cota-Gomez, Adela; Flores, Natalia C; Cruz, Coral et al. (2002) The human immunodeficiency virus-1 Tat protein activates human umbilical vein endothelial cell E-selectin expression via an NF-kappa B-dependent mechanism. J Biol Chem 277:14390-9
Piganelli, Jon D; Flores, Sonia C; Cruz, Coral et al. (2002) A metalloporphyrin-based superoxide dismutase mimic inhibits adoptive transfer of autoimmune diabetes by a diabetogenic T-cell clone. Diabetes 51:347-55
Gu, Y; Wu, R F; Xu, Y C et al. (2001) HIV Tat activates c-Jun amino-terminal kinase through an oxidant-dependent mechanism. Virology 286:62-71

Showing the most recent 10 out of 13 publications