| First Author | Zhang Z | Year | 2019 |
| Journal | Br J Pharmacol | Volume | 176 |
| Issue | 16 | Pages | 2945-2961 |
| PubMed ID | 31144304 | Mgi Jnum | J:294989 |
| Mgi Id | MGI:6458256 | Doi | 10.1111/bph.14745 |
| Citation | Zhang Z, et al. (2019) PPARdelta agonist prevents endothelial dysfunction via induction of dihydrofolate reductase gene and activation of tetrahydrobiopterin salvage pathway. Br J Pharmacol 176(16):2945-2961 |
| abstractText | BACKGROUND AND PURPOSE: Impaired endothelium-dependent relaxation (EDR) is a hallmark of endothelial dysfunction. A deficiency of tetrahydrobiopterin (BH4 ) causes endothelial NOS to produce ROS rather than NO. PPARdelta is an emerging target for pharmacological intervention of endothelial dysfunction. Thus, the present study examined the role of PPARdelta in the regulation of dihydrofolate reductase (DHFR), a key enzyme in the BH4 salvage pathway. EXPERIMENTAL APPROACH: Gene expression was measured by using qRT-PCR and western blotting. Biopterins and ROS were determined by using HPLC. NO was measured with fluorescent dye and electron paramagnetic resonance spectroscopy. Vasorelaxation was measured by Multi Myograph System. KEY RESULTS: The PPARdelta agonist GW501516 increased DHFR and BH4 levels in endothelial cells (ECs). The effect was blocked by PPARdelta antagonist GSK0660. Chromatin immunoprecipitation identified PPAR-responsive elements within the 5''''-flanking region of the human DHFR gene. The promoter activity was examined with luciferase assays using deletion reporters. Importantly, DHFR expression was suppressed by palmitic acid (PA, a saturated fatty acid) but increased by docosahexaenoic acid (DHA, a polyunsaturated fatty acid). GSK0660 prevented DHA-induced increased DHFR expression. Conversely, the suppressive effect of PA was mitigated by GW501516. In mouse aortae, GW501516 ameliorated the PA-impaired EDR. However, this vasoprotective effect was attenuated by DHFR siRNA or methotrexate. In EC-specific Ppard knockout mice, GW501516 failed to improve vasorelaxation. CONCLUSION AND IMPLICATIONS: PPARdelta prevented endothelial dysfunction by increasing DHFR and activating the BH4 salvage pathway. These results provide a novel mechanism for the protective roles of PPARdelta against vascular diseases. |
