Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways.
We investigated 18 AIDS hearts (5 with and 13 without cardiomyopathy) by using immunocytochemistry and computerized image analysis regarding the roles of HIV-1 proteins and tumor necrosis factor ligands in HIV cardiomyopathy (HIVCM). HIVCM and cardiomyocyte apoptosis were significantly related to each other and to the expression by inflammatory cells of gp120 and tumor necrosis factor-alpha. In HIVCM heart, active caspase 9, a component of the mitochondrion-controlled apoptotic pathway, and the elements of the death receptor-mediated pathway, tumor necrosis factor-alpha and Fas ligand, were expressed strongly on macrophages and weakly on cardiomyocytes. HIVCM showed significantly greater macrophage infiltration and cardiomyocyte apoptosis rate compared with non-HIVCM. HIV-1 entered cultured neonatal rat ventricular myocytes by macropinocytosis but did not replicate. HIV-1- or gp120-induced apoptosis of rat myocytes through a mitochondrion-controlled pathway, which was inhibited by heparin, AOP-RANTES, or pertussis toxin, suggesting that cardiomyocyte apoptosis is induced by signaling through chemokine receptors. In conclusion, in patients with HIVCM, cardiomyocytes die through both mitochondrion- and death receptor-controlled apoptotic pathways.
Twu
Cheryl
C
Department of Medicine, Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA 90073, USA.
Liu
Nancy Q
NQ
Popik
Waldemar
W
Bukrinsky
Michael
M
Sayre
James
J
Roberts
Jaclyn
J
Rania
Shammas
S
Bramhandam
Vishnu
V
Roos
Kenneth P
KP
MacLellan
W Robb
WR
Fiala
Milan
M
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D053222:Fas Ligand Protein; D005677:G(M1) Ganglioside / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008264:Macrophages; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology*; D010873:Pinocytosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018946:Chemokine CCL5; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D015699:HIV Envelope Protein gp120; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; C111989:aminooxypentane-RANTES; D005677:G(M1) Ganglioside; D006493:Heparin; D002784:Cholesterol