Elevated levels of heme oxygenase‐1 activity and mRNA in peripheral blood adherent cells of acquired immunodeficiency syndrome patients

Abstract

Patients with the acquired immunodeficiency syndrome (AIDS) commonly develop hematological abnormalities, including anemia, leukopenia, and thrombocytopenia. Heme synthesis and heme degradation are critical to the maintenance of cellular heme homeostasis and to hematopoietic differentiation. We examined heme oxygenase activity and expression of the heme oxygenase gene in adherent cells (monocytes-macrophages) obtained from the peripheral blood of AIDS patients and normal controls. Heme oxygenase activity in normal control cells was 43 +/- 16 pmol bilirubin formed/4 x 10(5) cells/hr as compared to 133 +/- 30 pmol bilirubin formed/4 x 10(5) cells/hr in the AIDS patients. Via blot hybridization analysis with human heme oxygenase cDNA, heme oxygenase mRNA levels in cells of the normal and the AIDS patients were compared. Total RNA from normal cells displayed only weak hybridization with the cDNA probe. In contrast, cells from peripheral blood of the AIDS patients displayed marked increases over normal levels in heme oxygenase mRNA. Heme oxygenase activity could be substantially suppressed by the competitive inhibitor of the enzyme, Sn-mesoporphyrin. Elevated heme oxygenase activity in cells of AIDS patients could produce a decrease in cellular heme needed for transductional signalling for the growth factor network, which regulates the hematopoietic microenvironment, and for other metabolic purposes. Suppression of heme catabolism by inhibitors of this enzyme may thus be useful in potentiating erythropoietic responses in this disorder.

Comparative Effects of Heme and Metalloporphyrins on Interferon- -Mediated Pathways in Monocytic Cells (THP-1)

“…The elevated levels of neopterin were ascribed to IFN-y stimulation of patients' macrophages (7). Additionally, in some instances, adherent cells from patients with HIV infection have elevated levels of heme oxygenase (38). Thus, it appears that fluctuations in the levels of IFN, heme,…”

Human Immunodeficiency Virus Type 1-Induced Macrophage Gene Expression Includes the p21 Gene, a Target for Viral Regulation

“…The enhanced transcription of genes involved in cellular recruitment, including genes for chemokines (interleukin-8 and MCP-1) and MRP14 as well as surface adhesion molecules, may favor host cell accumulation and syncytium formation (23,59). The metabolic pathway genes for dioxin-inducible cytochrome P450 (Table 1), which is associated with enhanced HIV-1 gene expression and the progression of AIDS (72), and heme oxygenase-1 (HO-1) (Table 1), a protein which is increased in the peripheral blood mononuclear cells of AIDS patients (34), were typically upregulated. In addition to HSP90 and HSP27, host molecules that have been implicated in the HIV-1 viral cycle (60, 65), HIF-1␣, a transcription factor that participates in the regulation of genes involved in angiogenesis, glucose metabolism, cell survival, and cancer (44), was also upregulated.…”

Pharmacological and Clinical Aspects of Heme Oxygenase

“…HIV infection caused induction of HO-1 by approximately 20-to 50-fold in peripheral blood mononuclear cells , which resulted in depletion of various heme proteins needed for the immune system. The mechanism by which HIV increases HO-1 is not proven but HIV-mediated increases in proinflammatory cytokines and oxidative stress have been attributed to up-regulation of HO-1 in the blood of patients with AIDS (Abraham et al, 1991b;Levere et al, 1993). However, an increase in heme levels caused inhibition of HIV reverse transcriptase Mingone et al, 2006).…”