Skip to main content
SpringerLink
Log in

HAART drugs induce mitochondrial damage and intercellular gaps and gp 120 causes apoptosis

  • Original Research
  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

HIV-1 infection is associated with serious cardiovascular complications, but the roles of HIV-1, viral proteins, and highly active antiretroviral therapy (HAART) drugs are not understood. HAART decreases the overall risk of heart disease but leads to metabolic disturbances and possibly coronary artery disease. We investigated toxicities of HIV-1, HIV-1 glycoprotein 120 (gp 120), and HAART drugs for human coronary artery endothelial cells (CAECs), brain microvascular endothelial cells, and neonatal rat ventricular myocytes (NRVMs). HIV-1 and gp 120, but not azidothymidine (AZT), induced apoptosis of NRVMs and CAECs. Ethylisothiourea, an inhibitor of nitric oxide synthase, inhibited apoptosis induction by gp 120. AZT, HIV-1, and gp 120 all damaged mitochondria of cardiomyocytes. HAART drugs, AZT, and indinavir, but not HIV-1, produced intercellular gaps between confluent endothelial cells and decreased transendothelial electrical resistance. In conclusion, HIV-1 and gp 120 induce toxicity through induction of cardiomyocyte and endothelial cell apoptosis. HAART drugs disrupt endothelial cell junctions and mitochondria and could cause vascular damage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Lewis, W. (2000). Cardiomyopathy in AIDS: a pathophysiological perspective. Prog. Cardiovasc. Dis. 43:151–170.

    Article  PubMed  CAS  Google Scholar 

  2. Koppel, K., Bratt, G., Eriksson, M., and Sandstrom, E. (2000). Serum lipid levels associated with increased risk for cardiovascular disease is associated with highly active antiretroviral therapy (HAART) in HIV-1 infection. Int. J. STD AIDS 11:451–455.

    Article  PubMed  CAS  Google Scholar 

  3. Barbaro, G. (2002). Cardiovascular manifestations of HIV infection. Circulation 106:1420–1425.

    Article  PubMed  Google Scholar 

  4. Liu, Q.N., Reddy, S., Sayre, J.W., Pop, V., Graves, M.C., and Fiala, M. (2001). Essential role of HIV type 1-infected and cyclooxygenase 2-activated macrophages and T cells in HIV type 1 myocarditis. AIDS Res. Hum. Retroviruses 17:1423–1433.

    Article  PubMed  CAS  Google Scholar 

  5. Barbaro, G., Di Lorenzo, G., Grisorio, B., and Barbarini, G. (1998). Cardiac involvement in the acquired immunodeficiency syndrome: a multicenter clinical-pathological study. Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS Investigators. AIDS Res. Hum. Retroviruses 14:1071–1077.

    PubMed  CAS  Google Scholar 

  6. Stein, J.H., Klein, M.A., Bellehumeur, J.L., McBride, P.E., Wiebe, D.A., Otvos, J.D., et al. (2001). Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation 104:257–262.

    PubMed  CAS  Google Scholar 

  7. Periard, D., Telenti, A., Sudre, P., Cheseaux, J.J., Halfon, P., Reymond, M.J., et al. (1999). Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation 100:700–705.

    PubMed  CAS  Google Scholar 

  8. Twu, C., Liu, N.Q., Popik, W., Bukrinsky, M., Sayre, J., Roberts, J., et al. (2002). Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways. Proc. Natl. Acad. Sci. USA 99:14386–14391.

    Article  PubMed  CAS  Google Scholar 

  9. Cicala, C., Arthos, J., Selig, S.M., Dennis, G. Jr., Hosack, D.A., Van Ryk, D., et al. (2002). HIV envelope induces a cascade of cell signals in non-proliferating target cells that favor virus replications. Proc. Natl. Acad. Sci. USA 99:9380–9385.

    Article  PubMed  CAS  Google Scholar 

  10. Izmailova, E., Bertley, F.M., Huang, Q., Makori, N., Miller, C.J., Young, R.A., et al. (2003). HIV-1 tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages. Nat. Med. 9:191–197.

    Article  PubMed  CAS  Google Scholar 

  11. Chen, D., Wang, M., Zhou, S., and Zhou, Q. (2002). HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim. EMBO J. 21:6801–6810.

    Article  PubMed  CAS  Google Scholar 

  12. Kinter, A.L., Umscheid, C.A., Arthos, J., Cicala, C., Lin, Y., Jackson, R., et al. (2003). HIV envelope induces virus expression from resting CD4+ T cells isolated from HIV-infected individuals in the absence of markers of cellular activation or apoptosis. J. Immunol. 170:2449–2455.

    PubMed  CAS  Google Scholar 

  13. Tobiume, M., Fujinaga, K., Suzuki, S., Komoto, S., Mukai, T., and Ikuta, K. (2002). Extracellular Nef protein activates signal transduction pathway from Ras to mitogen-activated protein kinase cascades that leads to activation of human immunodeficiency virus from latency. AIDS Res. Hum. Retroviruses 18:461–467.

    Article  PubMed  CAS  Google Scholar 

  14. Carr, A. and Cooper, D.A. (2000). Adverse effects of antiretroviral therapy. Lancet 356:1423–1430.

    Article  PubMed  CAS  Google Scholar 

  15. Reid, W., Sadowska, M., Denaro, F., Rao, S., Foulke, J. Jr., Hayes, N., et al. (2001). An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction. Proc. Natl. Acad. Sci. USA 98:9271–9276.

    Article  PubMed  CAS  Google Scholar 

  16. Kay, D.G., Yue, P., Hanna, Z., Jothy, S., Tremblay, E., and Jolicoeur, P. (2002). Cardiac disease in transgenic mice expressing human immunodeficiency virus-1 nef in cells of the immune system. Am. J. Pathol. 161:321–335.

    PubMed  CAS  Google Scholar 

  17. Raidel, S.M., Haase, C., Jansen, N.R., Russ, R.B., Sutliff, R.L., Velsor, L.W., et al. (2002). Targeted myocardial transgenic expression of HIV Tat causes cardiomyopathy and mitochondrial damage. Am. J. Physiol. Heart Circ. Physiol. 282:H1672–1678.

    PubMed  CAS  Google Scholar 

  18. Lewis, W., Simpson, J.F., and Meyer, R.R. (1994). Cardiac mitochondrial DNA polymerase-gamma is inhibited competitively and noncompetitively by phosphorylated zidovudine. Circ. Res. 74:344–348.

    PubMed  CAS  Google Scholar 

  19. Dalakas, M.C., Illa, I., Pezeshkpour, G.H., Laukaitis, J.P., Cohen, B., and Griffin, J.L. (1990). Mitochondrial myopathy caused by long-term zidovudine therapy. N. Engl. J. Med. 322:1098–1105.

    Article  PubMed  CAS  Google Scholar 

  20. Lipshultz, S.E., Easley, K.A., Orav, E.J., Kaplan, S., Starc, T.J., Bricker, J.T., et al. (2000). Absence of cardiac toxicity of zidovudine in infants: pediatric pulmonary and cardiac complications of vertically transmitted HIV infection study group. N. Engl. J. Med. 343:759–766.

    Article  PubMed  CAS  Google Scholar 

  21. Bozzette, S.A., Ake, C.F., Tam, H.K., Chang, S.W., and Louis, T.A. (2003). Cardiovaccular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N. Engl. J. Med. 348:702–710.

    Article  PubMed  CAS  Google Scholar 

  22. Moyle, G. and Carr, A. (2002). HIV-associated lipodystrophy metabolic complications, and antiretroviral toxicities. HIV Clin. Trials 3:89–98.

    PubMed  Google Scholar 

  23. Barbaro, G., Di Lorenzo, G., Cirelli, A., Grisorio, B., Lucchini, A., Hazra, C., et al. (2003). An open-label, prospective, observational study of the incidence of coronary artery disease in patients with HIV infection receiving highly active antiretroviral therapy. Clin. Ther. 25:2405–2418.

    Article  PubMed  CAS  Google Scholar 

  24. Oh, S.K., Cruikshank, W.W., Raina, J., Blanchard, G.C., Adler, W.H., Walker, J., et al. (1992). Identification of HIV-1 envelope glycoprotein in the serum of AIDS and ARC patients. J. Acquir. Immune Defic. Syndr. 5:251–256.

    PubMed  CAS  Google Scholar 

  25. Mossman, S.P., Bex, F., Berglund, P., Arthos, J., O'Neil, S.P., Riley, D., et al. (1996). Protection against lethal simian immunodeficiency virus SIV smmPBj14 disease by a recombinant Semliki Forest virus gp 160 vaccine and by a gp 120 subunit vaccine. J. Virol. 70:1953–1960.

    PubMed  CAS  Google Scholar 

  26. Liu, N.Q., Lossinsky, A.S., Popik, W., Li, X., Gujuluva, C., Kriederman, B., et al. (2002). Human immunodeficiency virus type 1 enters brain microvascular endothelia by macropinocytosis dependent on lipid rafts and the mitogen-activated protein kinase, signaling pathway. J. Virol. 76:6689–6700.

    Article  PubMed  CAS  Google Scholar 

  27. Gujuluva, C., Burns, A.R., Pushkarsky, T., Popik, W., Berger, O., Bukrinsky, M., et al. (2001). HIV-1 penetrates coronary artery endothelial cells by transcytosis. Mol. Med. 7:169–176.

    PubMed  CAS  Google Scholar 

  28. Garcia, J.G., Schaphorst, K.L., Verin, A.D., Vepa, S., Patterson, C.E., and Natarajan, V. (2000). Diperoxovanadate alters endothelial cell focal contacts and barrier function: role of tyrosine phosphorylation. J. Appl. Physiol. 89:2333–2343.

    PubMed  CAS  Google Scholar 

  29. Carr, A. (2000). HIV protease inhibitor-related lipodystrophy syndrome. Clin. Infect. Dis. 30(Suppl. 2):S135-S142.

    Article  PubMed  CAS  Google Scholar 

  30. Cioffi, D.L., Moore, T.M., Schaack, J., Creighton, J.R., Cooper, D.M., and Stevens, T. (2002). Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase. J. Cell Biol. 157:1267–1278.

    Article  PubMed  CAS  Google Scholar 

  31. Bogatcheva, N.V., Garcia, J.G., and Verin, A.D. (2002). Molecular mechanisms of thrombin-induced endothelial cell permeability. Biochemistry (Mosc.) 67:75–84.

    Article  CAS  Google Scholar 

  32. Wojciak-Stothard, B., Potempa, S., Eichholtz, T., and Ridley, A.J. (2001). Rho and Rac but not Cdc42 regulate endothelial cell permeability. J. Cell Sci. 114:1343–1355.

    PubMed  CAS  Google Scholar 

  33. Sandoval, R., Malik, A.B., Minshall, R.D., Kouklis, P., Ellis, C.A., and Tiruppathi, C. (2001). Ca(2+) signalling and PKC alpha activate increased endothelial permeability by disassembly of VE-cadherin junctions. J. Physiol. 533:433–445.

    Article  PubMed  CAS  Google Scholar 

  34. Borbiev, T., Garcia, J., and Verin, A.D. (2003). Role of phosphorylation of myosin- and actin-binding proteins in thrombin-induced permeability of endothelial cells. Russ. J. Bioorganic Chem. 29:464–470.

    Article  CAS  Google Scholar 

  35. Shi, S., Verin, A.D., Schaphorst, K.L., Gilbert-McClain, L.I., Patterson, C.E., Irwin, R.P., et al. (1998). Role of tyrosine phosphorylation in thrombin-induced endothelial cell contraction and barrier function. Endothelium 6:153–171.

    Article  PubMed  CAS  Google Scholar 

  36. Lewis, W., Haase, C.P., Raidel, S.M., Russ, R.B., Sutliff, R.L., Hoit, B.D., et al. (2001). Combined antiretroviral therapy causes cardiomyopathy and elevates plasma lactate in transgenic AIDS mice. Lab. Invest. 81:1527–1536.

    PubMed  CAS  Google Scholar 

  37. Narula, J., Haider, N., Virmani, R., DiSalvo, T.G., Kolodgie, F.D., Hajjar, R.J., et al. (1996). Apoptosis in myocytes in end-stage heart failure. N. Engl. J. Med. 335:1182–1189.

    Article  PubMed  CAS  Google Scholar 

  38. Barbaro, G., Di Lorenzo, G., Soldini, M., Giancaspro, G., Grisorio, B., Pellicelli, A., et al. (1999). Intensity of myocardial expression of inducible nitric oxide synthase influences the clinical course of human immunodeficiency virus-associated cardiomyopathy. Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS (GISCA). Circulation 100:933–939.

    PubMed  CAS  Google Scholar 

  39. Kroncke, K.D., Fehsel, K., Suschek, C., and Kolb-Bachofen, V. (2001). Inducible nitric oxide synthase-derived nitric oxide in gene regulation, cell death and cell survival. Int. Immunopharmacol. 1:1407–1420.

    Article  PubMed  CAS  Google Scholar 

  40. Kan, H., Xie, Z., and Finkel, M.S. (2000). HIV gp 120 enhances NO production by cardiac myocytes through p38 MAP kinase-mediated NF-kappaB activation. Am. J. Physiol. 279:H3138–3143.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Greater Los Angeles VA Medical Center, Los Angeles, CA

    Milan Fiala MD & Wendy Yang

  2. Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA, Los Angeles, CA

    Milan Fiala MD

  3. Molecular, Cellular and Developmental Biology, University of California, Molecular Biology Institute, Los Angeles, CA

    Thomas Murphy, Alfonso Luque & Luisa Iruela-Arispe

  4. Human BioMolecular Research Institute, San Diego, CA

    James MacDougall & John Cashman

  5. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA

    Georgette Buga & Russel E. Byrns

  6. Department of Medical Pathophysiology, University of Rome “La Sapienza,”, Rome, Italy

    Giuseppe Barbaro

  7. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

    James Arthos

Authors
  1. Milan Fiala MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James MacDougall
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wendy Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alfonso Luque
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luisa Iruela-Arispe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John Cashman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Georgette Buga
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Russel E. Byrns
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Giuseppe Barbaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. James Arthos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Milan Fiala MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fiala, M., Murphy, T., MacDougall, J. et al. HAART drugs induce mitochondrial damage and intercellular gaps and gp 120 causes apoptosis. Cardiovasc Toxicol 4, 327–337 (2004). https://doi.org/10.1385/CT:4:4:327

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/CT:4:4:327

Key Words

Search

Navigation