| First Author | Lakhkar A | Year | 2016 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 310 |
| Issue | 9 | Pages | H1107-17 |
| PubMed ID | 26921441 | Mgi Jnum | J:232922 |
| Mgi Id | MGI:5780474 | Doi | 10.1152/ajpheart.00961.2015 |
| Citation | Lakhkar A, et al. (2016) 20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition. Am J Physiol Heart Circ Physiol 310(9):H1107-17 |
| abstractText | 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-alpha gene (Tnfa), and 4) expression of tumor necrosis factor-alpha (TNF-alpha). Moreover, inhibition of G6PD increased protein kinase G1alpha activity, which, at least partially, mitigated superoxide production and Elk-1 and TNF-alpha 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. |
