Generation of hydrogen peroxide in resting and activated platelets

Maresca, M; Colao, Clorinda; Leoncini, Giuliana

doi:10.1002/cbf.290100203

Cited by 74 publications

(35 citation statements)

References 27 publications

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“…Thus, treatment of female rats with estradiol reduced protein content, enzyme activity, and messenger RNA of GRK 2 in the hypothalamus (Ansonoff and Etgen, 2001). On the other hand, the platelet aggregation (induced by epinephrine) and reactivity are increased in depressed patients (García-Sevilla et al, 1986, 1990Musselman et al, 1996Musselman et al, , 2000, and activated platelets produce reactive oxygen species, such as hydrogen peroxide (Maresca et al, 1992) that can modulate the expression of GRKs. Thus, the exposure of lymphocytes to hydrogen peroxide resulted in marked decreases in GRK 2 expression and in agonistinduced desensitization of b 2 -adrenoceptors (Lombardi et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Platelet α2A-Adrenoceptors, Gi Proteins and Receptor Kinases in Major Depression: Effects of Mirtazapine Treatment

Garcı́a-Sevilla

Ventayol

Pérez

et al. 2003

Neuropsychopharmacol

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Major depression is associated with the upregulation of a 2A -adrenoceptors in brain tissue and blood platelets. The homologous regulation of these receptors by G-protein-coupled receptor kinases (GRKs) might play a relevant role in the pathogenesis and treatment of depression. This study was designed to assess the status of the complex a 2A -adrenoceptor/Gai/GRK 2 in the platelets of depressed patients (n ¼ 22) before and after treatment with the antidepressant mirtazapine, an antagonist at a 2A -adrenoceptors (30-45 mg/day for up to 6 months). A second series of depressed suicide attempters (n ¼ 32) were also investigated to further assess the status of platelet GRK 2 and GRK 6. Platelet a 2A -adrenoceptors and Gai protein immunoreactivities were increased in depressed patients (49 and 35%) compared with matched controls. In contrast, GRK 2 content was decreased in the two series of depressed patients (27 and 28%). GRK 6 (a GRK with different properties) was found unchanged. In drug-free depressed patients, the severity of depression (behavioral ratings with two different instruments) correlated inversely with the content of platelet GRK 2 (r ¼ À0.46, n ¼ 22, p ¼ 0.032, and r ¼ À0.55, n ¼ 22, p ¼ 0.009). After 4-24 weeks of treatment, mirtazapine induced downregulation of platelet a 2A -adrenoceptors (up to 34%) and Gai proteins (up to 28%), and the upregulation of GRK 2 (up to 30%). The results indicate that major depression is associated with reduced platelet GRK 2, suggesting that a defect of this kinase may contribute to the observed upregulation of a 2A -adrenoceptors. Moreover, treatment with mirtazapine reversed this abnormality and induced downregulation of a 2A -adrenoceptor/Gai complex. The results support a role of supersensitive a 2A -adrenoceptors in the pathogenesis and treatment of major depression.

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Section: Discussionmentioning

confidence: 99%

Regulation of Platelet α2A-Adrenoceptors, Gi Proteins and Receptor Kinases in Major Depression: Effects of Mirtazapine Treatment

Garcı́a-Sevilla

Ventayol

Pérez

et al. 2003

Neuropsychopharmacol

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“…In those studies it was also shown that NO, hydroxyl radical (OH × ) and metal ions do not oxidize 2,7-dichlorofluorescin. Some earlier reports have suggested that hydrogen peroxide also oxidized 2,7-dichlorofluorescin [12]. To test this, we incubated DCFDA (5 mmol/l) with either 100 mmol/l H 2 O 2 or 100 mmol/l ONOO ± for 15 min in PBS at 37°C.…”

Section: Methodsmentioning

confidence: 97%

Evidence for iNOS-dependent peroxynitrite production in diabetic platelets

et al. 1999

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Nitric oxide (NO), an important mediator of both physiological and pathological processes [1], is derived from l-arginine by a family of enzymes termed NO synthases [2]. At least three isoforms of NO synthase (NOS) have been detected. Of these, endothelial (eNOS) and neuronal (nNOS) enzymes are constitutive and regulated by Ca 2+ /calmodulin. The inducible NOS (iNOS) originally detected in macrophages and in the endothelium is produced in response to cytokines and cellular debris of microbial origin. This inducible form can produce 10-to 50-fold more NO than the constitutive NOS. In addition, Diabetologia (1999) Abstract Aims/hypothesis. The aim of the present study was twofold. Firstly, to determine whether diabetic platelets produce more peroxynitrite than normal platelets and secondly to correlate the peroxynitrite production with the intraplatelet induction of the inducible isoform of nitric oxide-synthase. Methods. Intraplatelet peroxynitrite production was monitored with dichlorofluorescin acetate with a combination of confocal microscopy and steady-state fluorescence. The platelets were probed for the induction of the inducible-nitric oxide-synthase by western immunoblotting.Results. In the presence of extracellular l-arginine (100 mmol/l), platelets from subjects with Type I (insulin-dependent) diabetes displayed about 5 times higher fluorescence than those from control subjects. To determine whether inducible-nitric oxide-synthase was the source of peroxynitrite, dichlorofluorescein production was quantified as a function of larginine as well as nitric oxide-synthase inhibitors, in platelets from control subjects, subjects with Type I diabetes and subjects with Type II (non-insulin-dependent) diabetes mellitus. Platelets from subjects with Type I yielded about sevenfold and those from Type II about threefold larger amounts of l-arginine/nitric oxide-synthase-dependent dichlorofluorescein fluorescence than those from control subjects. The platelets were then immunologically probed for inducible-nitric oxide-synthase, which has previously been implicated in peroxynitrite production and detected in megakaryocytes of subjects with coronary heart disease. Western immunoblots of intraplatelet proteins indicated that the inducible-nitric oxide-synthase was absent in control subjects. Platelets from both Type I and Type II diabetic subjects, however, contained inducible-nitric oxide-synthase. Conclusion/interpretation. Inducible-nitric oxide-synthase-derived peroxynitrite is a source of platelet damage in diabetes. [Diabetologia (1999) 42: 539± 544]

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“…The effect of increasing or lowering cellular GSH levels on kinamycin F-induced DNA strand breaks was also determined. In these parallel experiments K562 cells were pre-incubated with either OTC (5 mM ) or BSO (100 μM) for either 24 …”

Section: Fast Micromethods Dna Single-strand-break Assaymentioning

confidence: 99%

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

O’Hara

Patel

et al. 2007

Free Radical Biology and Medicine

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The bacterial metabolite kinamycin F, which is being investigated as a potent antitumor agent, contains an unusual and potentially reactive diazo group as well as a paraquinone and a phenol functional group. Kinamycin F reacted with glutathione (GSH) in a complex series of reactions which suggested that kinamycin F may have its cytotoxicity modulated by GSH. Consistent with this idea 2-oxo-4-thiazolidinecarboxylic acid treatment to increase cellular GSH levels and buthionine sulfoximine treatment to decrease GSH levels resulted in decreased and increased kinamycin F cytotoxicity, respectively, in K562 leukemia cells. Kinamycin F weakly bound to DNA and induced DNA damage in K562 cells that was independent of GSH levels. The GSH-promoted DNA nicking induced by kinamycin F in vitro was attenuated by deferoxamine, dimethyl sulfoxide, and by catalase, which indicated that DNA damage initiated by this agent occurred in an iron-, hydrogen peroxideand hydroxyl radical-dependent manner. Electron paramagnetic resonance spectroscopy experiments showed that the GSH/kinamycin F system produced a semiquinone free radical and that the hydrogen peroxide/peroxidase/kinamycin F system generated a phenoxyl free radical. In conclusion, the results indicated that kinamycin F cytotoxicity may be due to reductive and/or peroxidative activation to produce DNA-and protein-damaging species.

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Generation of hydrogen peroxide in resting and activated platelets

Cited by 74 publications

References 27 publications

Regulation of Platelet α2A-Adrenoceptors, Gi Proteins and Receptor Kinases in Major Depression: Effects of Mirtazapine Treatment

Regulation of Platelet α2A-Adrenoceptors, Gi Proteins and Receptor Kinases in Major Depression: Effects of Mirtazapine Treatment

Evidence for iNOS-dependent peroxynitrite production in diabetic platelets

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

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