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HO Inhibitor (ho + inhibitor)
Selected AbstractsAstroglia overexpressing heme oxygenase-1 predispose co-cultured PC12 cells to oxidative injury,JOURNAL OF NEUROSCIENCE RESEARCH, Issue 10 2007Linyang Song Abstract The mechanisms responsible for the progressive degeneration of dopaminergic neurons and pathologic iron deposition in the substantia nigra pars compacta of patients with Parkinson's disease (PD) remain unclear. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in the oxidative degradation of heme to ferrous iron, carbon monoxide, and biliverdin, is upregulated in affected PD astroglia and may contribute to abnormal mitochondrial iron sequestration in these cells. To determine whether glial HO-1 hyper-expression is toxic to neuronal compartments, we co-cultured dopaminergic PC12 cells atop monolayers of human (h) HO-1 transfected, sham-transfected, or non-transfected primary rat astroglia. We observed that PC12 cells grown atop hHO-1 transfected astrocytes, but not the astroglia themselves, were significantly more susceptible to dopamine (1 ,M) + H2O2 (1 ,M)-induced death (assessed by nuclear ethidium monoazide bromide staining and anti-tyrosine hydroxylase immunofluorescence microscopy) relative to control preparations. In the experimental group, PC12 cell death was attenuated significantly by the administration of the HO inhibitor, SnMP (1.5 ,M), the antioxidant, ascorbate (200 ,M), or the iron chelators, deferoxamine (400 ,M), and phenanthroline (100 ,M). Exposure to conditioned media derived from HO-1 transfected astrocytes also augmented PC12 cell killing in response to dopamine (1 ,M) + H2O2 (1 ,M) relative to control media. In PD brain, overexpression of HO-1 in nigral astroglia and accompanying iron liberation may facilitate the bioactivation of dopamine to neurotoxic free radical intermediates and predispose nearby neuronal constituents to oxidative damage. © 2007 Wiley-Liss, Inc. [source] Role of Vascular Heme Oxygenase in Reduced Myogenic Reactivity Following Chronic HypoxiaMICROCIRCULATION, Issue 2 2006JAY S. NAIK ABSTRACT Objective: Exposure to chronic hypoxia (CH) results in a persistent endothelium-dependent vascular smooth muscle hyperpolarization that diminishes vasoconstrictor reactivity. Experiments were performed to test the hypothesis that products of both cytochrome P450 epoxygenase (CYP) and heme oxygenase (HO) are required for the persistent diminished myogenic reactivity following CH. Methods: The authors examined myogenic responses of mesenteric arteries isolated from control and CH (48 h; PB = 380 mmHg) rats in the presence of a HO inhibitor (zinc protoporphyrin IX; ZnPPIX) or combined HO and CYP epoxygenase inhibition (sulfaphenazole). Arteries were isolated and cannulated and the vascular smooth muscle was loaded with the Ca2 + indicator Fura-2. Results: Control vessels maintained their internal diameter in response to step increases in intraluminal pressure, whereas arteries from CH animals passively distended. ZnPPIX augmented myogenic reactivity and [Ca2 +] in arteries from CH animals. Combined administration of sulfaphenazole and ZnPPIX did not have an additional effect compared to ZnPPIX alone. Myogenic reactivity in control vessels was not altered by ZnPPIX or ZnPPIX + sulfaphenazole. Conclusions: HO appears to play a role in regulating myogenic reactivity following CH. Furthermore, these data suggest that products of HO and CYP are both required for the observed attenuation in vasoreactivity following CH. [source] Protective Effects of Ischemic Preconditioning on the Intestinal Mucosal Microcirculation Following Ischemia,Reperfusion of the IntestineMICROCIRCULATION, Issue 8 2005ISMAIL H. MALLICK ABSTRACT Objective: The small bowel villi are extremely sensitive to ischemia,reperfusion (IR) injury and a range of microcirculatory disturbances contribute to structural and functional changes. The aim of this study was to determine the protective effects of ischemic preconditioning (IPC) of the intestine on the mucosal villous microcirculation during IR injury of the intestine and whether heme oxygenase (HO) is involved in the protection. Methods: Rats were allocated into 4 groups: (1) sham, (2) IR consisting of 30 min of ischemia followed by 2 h of reperfusion, (3) IPC, as in IR group, but preceded by 10 min of ischemia and 10 min of reperfusion, and (4) with administration of zinc protoporphyrin, an HO inhibitor before IPC and IR. The mucosa of an exteriorized segment of ileum was visualized. Mucosal perfusion index (MPI), red blood cell (RBC) velocity and leukocyte,endothelial interactions during reperfusion were assessed continuously using in vivo fluorescence microscopy. HO activity in the ileum was assessed at the end of the reperfusion period. Results: IPC improved the MPI by 26% and the RBC velocity by 29% on comparison to IR. IR led to a 52% increase in leukocyte,endothelial interactions on comparison to IPC. The administration of zinc protoporphyrin reversed the beneficial effects of IPC. There was a two fold increase of HO activity in IPC compared to IR, whereas zinc protoporphyrin significantly reduced the HO activity. Conclusions: IPC conferred a protective effect on the villous microcirculation possibly via HO and might prove to be an effective strategy for the amelioration of IR injury. [source] Effect of HO-1 cDNA-liposome complex transfer on erectile signalling of aged ratsANDROLOGIA, Issue 3 2009M. T. Abdel Aziz Summary This work aimed to assess the efficacy of haeme oxygenase-1 (HO-1) cDNA-liposome complex transfer as a mediator of erectile signalling in aged rats. One hundred and fifty aged white albino rats were equally divided into five groups: controls, rats receiving lipofectamine, rats receiving intracorporeal HO-1 cDNA-lipsome complex, rats receiving HO-1 cDNA-liposome complex plus nitric oxide synthase (NOS) inhibitor, and rats receiving HO-1 cDNA-liposome complex plus HO inhibitor. Six rats were killed from each group after 12, 24 and 48 h, and after1 and 2 weeks. In dissected cavernous tissues, the following were assessed: HO-1 gene expression, Western blot for HO-1, HO enzyme activity, cGMP and histopathology. The results showed that HO-1 cDNA-liposome complex transfer led to a significant increase in cavernous tissue HO-1 protein, HO-1 gene expression, HO enzyme activity and cGMP up to 1 week. NOS inhibition exhibited no effect on HO-1 gene enhancement of cavernous tissue HO enzyme activity or cGMP, whereas inhibition of HO significantly decreased these parameters. Histopathology of cavernous tissue demonstrated a significant dilatation of helicine arteries in HO-1 cDNA-liposome complex treated group after 48 h compared with the controls. It is concluded that HO-1 cDNA-liposome complex transfer augments cavernous tissue cGMP with subsequent sinusoidal relaxation. [source] Brazilin and the extract from Caesalpinia sappan L. protect oxidative injury through the expression of heme oxygenase-1BIOFACTORS, Issue 3 2007Byung-Min Choi Abstract In this study, we examined the protective effects of Caesalpinia sappan L. and its major component, brazilin, against tert-butylhydroperoxide (t-BHP)-induced cell death in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. We found that the extract of C. sappan L. and brazilin induced antioxidant response element (ARE)-luciferase activity and heme oxygenase-1 (HO-1) expression in a concentration-dependent manner. The inductive effect of brazilin was more potent than the extract of C. sappan L. and the expression of HO-1 reached a peak at 12 h after brazilin treatment. The extract and brazilin protected the cells against t-BHP-induced cell death. Their protective effects were abrogated by zinc protoporphyrin IX (ZnPP IX), a HO inhibitor. These results demonstrate that the extract of C. sappan L. and brazilin induce the expression of HO-1 and the enzyme diminishes t-BHP-induced cell death in HEI-OC1 cells. [source] Selectivity of imidazole,dioxolane compounds for in vitro inhibition of microsomal haem oxygenase isoformsBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2006Robert T Kinobe Haem oxygenases (HO) are involved in the catalytic breakdown of haem to generate carbon monoxide (CO), iron and biliverdin. It is widely accepted that products of haem catabolism are involved in biological signaling in many physiological processes. Conclusions to most studies in this field have gained support from the judicious use of synthetic metalloporphyrins such as chromium mesoporphyrin (CrMP) to selectively inhibit HO. However, metalloporphyrins have also been found to inhibit other haem-dependent enzymes, such as nitric oxide synthase (NOS), cytochromes P-450 (CYPs) and soluble guanylyl cyclase (sGC), induce the expression of HO-1 or exhibit varied toxic effects. To obviate some of these problems, we have been examining non-porphyrin HO inhibitors and the present study describes imidazole,dioxolane compounds with high selectivity for inhibition of HO-1 (rat spleen microsomes) compared to HO-2 (rat brain microsomes) in vitro. (2R,4R)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H -imidazol-1-yl)methyl]-4-methyl-1,3-dioxolane hydrochloride) was identified as the most selective inhibitor with a concentration of 0.6 ,M inhibiting HO-1(inducible) by 50% compared with 394 ,M for HO-2 (constitutive). These compounds were found to have no effects on the catalytic activities of rat brain NOS and lung sGC, but were potent inhibitors of microsomal CYP2E1 and CYP3A1/3A2 activities. In conclusion, we have identified imidazole,dioxolanes that are able to inhibit microsomal HO in vitro with high selectivity for HO-1 compared to HO-2, and little or no effect on the activities of neuronal NOS and sGC. These molecules could be used to facilitate studies on the elucidation of physiological roles of HO/CO in biological systems. British Journal of Pharmacology (2006) 147, 307,315. doi:10.1038/sj.bjp.0706555 [source] | |||||||||||||