Enhanced Depolarization-Induced Pulmonary Vasoconstriction Following Chronic Hypoxia Requires EGFR-Dependent Activation of NAD(P)H Oxidase 2
| Autor: | Charles E. Norton, Nikki L. Jernigan, Bradley Rs Broughton, Benjimen R. Walker, Thomas C. Resta |
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| Rok vydání: | 2013 |
| Předmět: |
Male
rac1 GTP-Binding Protein medicine.medical_specialty Vascular smooth muscle Calcium Channels L-Type Physiology Clinical Biochemistry Pulmonary Artery Biochemistry Muscle Smooth Vascular Membrane Potentials Potassium Chloride chemistry.chemical_compound Internal medicine Hypoxic pulmonary vasoconstriction medicine Animals Vasoconstrictor Agents Hypoxia Molecular Biology General Environmental Science Forum Original Research Communications Membrane Glycoproteins Superoxide NADPH Oxidases Depolarization Hydrogen Peroxide Cell Biology Hypoxia (medical) Rats ErbB Receptors Endocrinology chemistry Vasoconstriction NAD(P)H oxidase NADPH Oxidase 2 Apocynin cardiovascular system General Earth and Planetary Sciences Calcium medicine.symptom circulatory and respiratory physiology |
| Zdroj: | Antioxidants & Redox Signaling. 18:1777-1788 |
| ISSN: | 1557-7716 1523-0864 |
| DOI: | 10.1089/ars.2012.4836 |
| Popis: | Aims: Chronic hypoxia (CH) enhances depolarization-induced myofilament Ca2+ sensitization and resultant pulmonary arterial constriction through superoxide (O2−)-dependent stimulation of RhoA. Because NAD(P)H oxidase (NOX) has been implicated in the development of pulmonary hypertension, we hypothesized that vascular smooth muscle (VSM) depolarization increases NOX-derived O2− production leading to myofilament Ca2+ sensitization and augmented vasoconstrictor reactivity following CH. As epidermal growth factor receptor (EGFR) mediates Rac1-dependent NOX activation in renal mesangial cells, we further sought to examine the role EGFR plays in this response. Results: Vasoconstrictor responses to depolarizing concentrations of KCl were greater in lungs isolated from CH (4 wk, 0.5 atm) rats compared to normoxic controls, and this effect of CH was abolished by the general NOX inhibitor, apocynin. CH similarly augmented KCl-induced vasoconstriction and O2− generation (assessed using the fluorescent indicator, dihydroethidium) in Ca2+-permeabilized, pressurized small pulmonary arteries. These latter responses to CH were prevented by general inhibition of NOX isoforms (apocynin, diphenylene iodonium), and by selective inhibition of NOX 2 (gp91ds-tat), Rac1 (NSC 23766), and EGFR (AG 1478). Consistent with these observations, CH increased KCl-induced EGFR phosphorylation, and augmented depolarization-induced Rac1 activation in an EGFR-dependent manner. Innovation: This study establishes a novel signaling axis in VSM linking membrane depolarization to contraction that is independent of Ca2+ influx, and which mediates myofilament Ca2+ sensitization in the hypertensive pulmonary circulation. Conclusion: CH augments membrane depolarization-induced pulmonary VSM Ca2+ sensitization and vasoconstriction through EGFR-dependent stimulation of Rac1 and NOX 2. Antioxid. Redox Signal. 18, 1777–1788. |
| Databáze: | OpenAIRE |
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