Nox2 as a potential target of mitochondrial superoxide and its role in endothelial oxidative stress
| Autor: | Anna Dikalova, Sergey Dikalov, Alfiya Bikineyeva, Rafal R. Nazarewicz |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Potassium Channels
Physiology Vasodilator Agents Cell Respiration Blood Pressure Mitochondrion medicine.disease_cause Mice chemistry.chemical_compound Superoxides Physiology (medical) Diazoxide medicine Animals Humans Aorta Cells Cultured Membrane Potential Mitochondrial Electron Transport Complex I Membrane Glycoproteins NADPH oxidase biology Superoxide Electron Transport Complex II Endothelial Cells NADPH Oxidases NOX4 Molecular biology Mitochondria Oxidative Stress chemistry NOX1 NADPH Oxidase 2 Call for Papers biology.protein ATP–ADP translocase Cardiology and Cardiovascular Medicine Oxidative stress medicine.drug |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 305:H1131-H1140 |
| ISSN: | 1522-1539 0363-6135 |
| DOI: | 10.1152/ajpheart.00063.2013 |
| Popis: | Superoxide (O2·−) production by the NADPH oxidases is implicated in the pathogenesis of many cardiovascular diseases, including hypertension. We have previously shown that activation of NADPH oxidases increases mitochondrial O2·−which is inhibited by the ATP-sensitive K+channel (mitoKATP) inhibitor 5-hydroxydecanoic acid and that scavenging of mitochondrial or cytoplasmic O2·−inhibits hypertension. We hypothesized that mitoKATP-mediated mitochondrial O2·−potentiates cytoplasmic O2·−by stimulation of NADPH oxidases. In this work we studied Nox isoforms as a potential target of mitochondrial O2·−. We tested contribution of reverse electron transfer (RET) from complex II to complex I in mitochondrial O2·−production and NADPH oxidase activation in human aortic endothelial cells. Activation of mitoKATPwith low dose of diazoxide (100 nM) decreased mitochondrial membrane potential (tetramethylrhodamine methyl ester probe) and increased production of mitochondrial and cytoplasmic O2·−measured by site-specific probes and mitoSOX. Inhibition of RET with complex II inhibitor (malonate) or complex I inhibitor (rotenone) attenuated the production of mitochondrial and cytoplasmic O2·−. Supplementation with a mitochondria-targeted SOD mimetic (mitoTEMPO) or a mitochondria-targeted glutathione peroxidase mimetic (mitoEbselen) inhibited production of mitochondrial and cytoplasmic O2·−. Inhibition of Nox2 (gp91ds) or Nox2 depletion with small interfering RNA but not Nox1, Nox4, or Nox5 abolished diazoxide-induced O2·−production in the cytoplasm. Treatment of angiotensin II-infused mice with RET inhibitor dihydroethidium (malate) significantly reduced blood pressure. Our study suggests that mitoKATP-mediated mitochondrial O2·−stimulates cytoplasmic Nox2, contributing to the development of endothelial oxidative stress and hypertension. |
| Databáze: | OpenAIRE |
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