Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways

Abstract

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-␣. 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-␣ 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.

Cardiovascular complications in the acquired immunodeficiency syndrome

“…Endothelial activation in HIV-1 infection may also be caused by cytokines (e.g., TNF-alpha) secreted in response to mononuclear or adventitial cell activation by the virus, or may be a direct effect of the secreted HIV-1-associated proteins gp 120 and tat (transactivator of viral replication) on the endothelium with possible induction of apoptosis process 37 . Opportunistic agents, such as cytomegalovirus, as well as human herpes virus-8 (a virus involved in the development of AIDS-associated Kaposi's sarcoma), frequently co-infect HIV-infected patients and may contribute to development of endothelial damage.…”

Mechanisms of apoptosis induction by the HIV-1 envelope

“…Soluble gp120 can induce apoptosis in lymphocytes, 12 but also in neurones, [24][25][26][27] cardiomyocytes, 17,28 kidney epithelial cells 29,30 and hepatocytes. 31 These potent cytotoxic effects have been implicated in the HIV-1-induced lymphodepletion, HIV-associated dementia (also called HIV encephalitis or neuro-AIDS), AIDS-cardiomyopathy, as well as AIDS associated nephropathy and hepatopathy.…”

“…32 Cell lines transfected with a truncated form of CD4 that binds gp120 but lacks the ability to transduce signals (due to absence of the cytoplasmic domain of CD4), still manifest DCm dissipation in response to gp120 acting on CXCR4. 16 The signal triggered by gp120 involves chemokine receptorsin neurons mainly CXCR4, 16,17 and downstream of such receptors, pertussis toxin-sensitive G proteins, 17 the p38 mitogen-activated protein kinase pathway, 38 and/or a rapid cytosolic Ca 2 þ increase 39 ( Figure 2). Gp120 induces apoptosis of cultured neurons and sensitizes them to oxidative stress and excitotoxins.…”

“…[12][13][14][15] The Env glycoprotein (gp) precursor protein (gp160) undergoes proteolytic maturation to generate gp41 (membrane inserted) and gp120 (membrane inserted or shed from the cell surface). Soluble gp120 can stimulate proapoptotic signal via an action on chemokine receptors (CXCR4 for lymphotropic Env variants, CCR5 for monocytotropic Env variants) 12,16,17 (Figure 1). Although soluble gp120 has been detected in body fluids, it has been doubted whether it would reach concentrations high enough to induce cell death in vivo.…”

Linaje y muerte celular programadas: implicaciones en la biología del desarrollo y en biomedicina.

“…Este conocimiento tiene un gran impacto sobre todos los aspectos de la viabilidad, la cinética y el equilibrio celular de los tejidos y órganos de los animales. Los análisis de tejidos post mortem de pacientes y animales, así como los estudios experimentales con cultivos de células cardiacas, neuronas, células del sistema linfático y hematopoyético, entre otras, que han servido de modelos experimentales de la patogénesis de enfermedades humanas, han indicado la existencia de la muerte celular programada disminuida, por ejemplo, en cáncer, o excesiva, como en algunas enfermedades cardiovasculares y neurodegenerativas (8)(9)(10)(11)(12)(13). Por tanto, el conocimiento de los mecanismos moleculares que regulan la viabilidad celular ha abierto nuevas posibilidades para el tratamiento de enfermedades en cuyo mecanismo está implicado un aumento o una disminución de la muerte celular programada.…”