Induction of the Heme Oxygenase-1 Gene by Metalloporphyrins

Luo

The American Journal of Pathology

et al. 2009

158

151

Oxidative stresses are believed to play an important role in the induction of both cell adhesion molecules and pro-inflammatory cytokines, a key event in a variety of inflammatory processes. The enzyme heme oxygenase-1 (HO-1) functions as an antioxidant and serves to protect against tissue injury. In this study, we report that HO-1 was induced in cultured human tracheal smooth muscle cells after either treatment with a potent inducer of HO-1 activity, cobalt protoporphyrin IX, or infection with a recombinant adenovirus that carries the human HO-1 gene. Overexpression of HO-1 protected against tumor necrosis factor (TNF)-␣-mediated airway inflammation via the down-regulation of oxidative stress, adhesion molecules, and interleukin-6 in both cultured human tracheal smooth muscle cells and the airways of mice. In addition, HO-1 overexpression inhibited TNF-␣-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, adherence of THP-1 cells, generation of interleukin-6, p47 phox translocation, and nuclear factor-B activation. HO-1 overexpression also attenuated TNF-␣-induced oxidative stress, which was abrogated in the presence of both the HO-1 inhibitor, zinc protoporphyrin IX, as well as a carbon monoxide scavenger. In addition, HO-1 overexpression reduced the formation of a TNFR1/c-Src/p47 phox complex. These results suggest that HO-1 functions as a suppressor of TNF-␣ signaling, not only by inhibiting the expression of adhesion molecules and generation of interleukin-6, but also by diminishing intracellular reactive oxygen species production and nuclear factor-B activation in both cultured human tracheal smooth muscle cells and the airways of mice.

Section: Copp IX Induces Ho-1 Expression and Activity Through Nrf2 Insupporting

confidence: 82%

Section: Discussionmentioning

confidence: 51%

Overexpression of HO-1 Protects against TNF-α-Mediated Airway Inflammation by Down-Regulation of TNFR1-Dependent Oxidative Stress

Luo

The American Journal of Pathology

et al. 2009

158

151

“…Recently, several signaling pathways, including MAPKs and PI3K, 15 have been implicated in the nuclear translocation and activation of Nrf2. Therefore, to further elucidate the mechanisms by which flunarizine induces the nuclear translocation of Nrf2, we examined the effect of flunarizine on MAPKs, including JNK, 16 ERK and p38, 17 and PI3K-Akt kinase. The phosphorylation of JNK, ERK and p38 proteins was not apparent in cells treated with flunarizine alone.…”

Section: Flunarizine Dramatically Increased the Nuclear Translocationmentioning

confidence: 99%

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Kim

et al. 2006

Cell Death Differ

We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GSTl-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.

“…Multiple lines of evidence support the idea that biliverdin, bilirubin, and CO contribute to the physiological functions of HO-1, including anti-oxidative, anti-inflammatory, anti-proliferative, and anti-apoptotic effects (21)(22)(23)(24)(25)(26)(27). HO-1 is widely distributed in tissues and robustly induced in many cells by its substrate heme (28)(29)(30) and by numerous stressful stimuli such as ultraviolet radiation, heat shock, inflammation, hypoxia, and various oxidative agents (31)(32)(33)(34)(35)(36)(37). The physiological function of HO-1 has been confirmed by observations in HO-1 knockout mice (38;39) and in one child, the product of a consanguineous mating, with severe genetic deficiency of HO-1 activity (40;41).…”

mentioning

confidence: 95%

Reciprocal Effects of Micro-RNA-122 on Expression of Heme Oxygenase-1 and Hepatitis C Virus Genes in Human Hepatocytes

et al. 2007

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