20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition
| Autor: | Michael S. Wolin, Katherine H. Gotlinger, Vidhi Dhagia, Anand Lakhkar, Dhara Patel, Sachindra R. Joshi, Michal L. Schwartzman, Dong Sun, Sachin A. Gupte |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Vascular smooth muscle Physiology Anti-Inflammatory Agents Aorta Thoracic 030204 cardiovascular system & hematology Muscle Smooth Vascular Rats Sprague-Dawley Pathogenesis chemistry.chemical_compound 0302 clinical medicine Superoxides Hydroxyeicosatetraenoic Acids Enzyme Inhibitors Extracellular Signal-Regulated MAP Kinases Superoxide Phenotype cardiovascular system Call for Papers lipids (amino acids peptides and proteins) Tumor necrosis factor alpha Cytochrome P-450 CYP4A Inflammation Mediators Signal transduction medicine.symptom Cardiology and Cardiovascular Medicine Signal Transduction medicine.medical_specialty Genotype Myocytes Smooth Muscle Inflammation Glucosephosphate Dehydrogenase Pulmonary Artery Biology 03 medical and health sciences Physiology (medical) Internal medicine Cyclic GMP-Dependent Protein Kinases medicine Animals Glucose-6-phosphate dehydrogenase ets-Domain Protein Elk-1 Tumor Necrosis Factor-alpha Molecular biology Mice Mutant Strains Mitochondria Muscle MicroRNAs 030104 developmental biology Endocrinology chemistry Mutation Cattle cGMP-dependent protein kinase |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 310:H1107-H1117 |
| ISSN: | 1522-1539 0363-6135 |
| Popis: | 20-Hydroxyeicosatetraeonic acid (20-HETE) produced by cytochrome P-450 monooxygenases in NADPH-dependent manner is proinflammatory, and it contributes to the pathogenesis of systemic and pulmonary hypertension. In this study, we tested the hypothesis that inhibition of glucose-6-phosphate dehydrogenase (G6PD), a major source of NADPH in the cell, prevents 20-HETE synthesis and 20-HETE-induced proinflammatory signaling that promotes secretory phenotype of vascular smooth muscle cells. Lipidomic analysis indicated that G6PD inhibition and knockdown decreased 20-HETE levels in pulmonary arteries as well as 20-HETE-induced 1) mitochondrial superoxide production, 2) activation of mitogen-activated protein kinase 1 and 3, 3) phosphorylation of ETS domain-containing protein Elk-1 that activate transcription of tumor necrosis factor-α gene ( Tnfa), and 4) expression of tumor necrosis factor-α (TNF-α). Moreover, inhibition of G6PD increased protein kinase G1α activity, which, at least partially, mitigated superoxide production and Elk-1 and TNF-α expression. Additionally, we report here for the first time that 20-HETE repressed miR-143, which suppresses Elk-1 expression, and miR-133a, which is known to suppress synthetic/secretory phenotype of vascular smooth muscle cells. In summary, our findings indicate that 20-HETE elicited mitochondrial superoxide production and promoted secretory phenotype of vascular smooth muscle cells by activating MAPK1-Elk-1, all of which are blocked by inhibition of G6PD. |
| Databáze: | OpenAIRE |
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