gw0742 and Hypoxia

This study aimed to investigate the effects of PPAR-β/δ receptor agonist GW0742 on neuroinflammation in a rat model of hypoxia-ischaemia (HI) and in PC12 cells in OGD model. HI was induced by ligating the common carotid artery and inducing hypoxia for 150 minutes. Immunofluorescence was used for quantification of microglia activation and for determining cellular localization of PPAR-β/δ. Expression of proteins was measured by Western blot. Activation of miR-17-5p by GW0742 was assessed in PC12 cells by Dual-Luciferase Reporter Gene Assay. The endogenous expression of TXNIP, NLRP3, cleaved caspase-1 and IL-1β was increased after HI. GW0742 treatment significantly reduced the number of activated pro-inflammatory microglia in ipsilateral hemisphere after HI. Mechanistically, GW0742 significantly decreased the expression of TXNIP, NLRP3, IL-6 and TNF-α. Either PPAR-β/δ antagonist GSK3787, miR-17-5p inhibitor, or TXNIP CRISPR activation abolished the anti-inflammatory effects of GW0742. Activation of PPAR-β/δ by GW0742 activated miR-17-5p expression in PC12 cells and increased cell viability after OGD, which was accompanied by decreased expression of TXNIP and reduced secretion of IL-1β and TNF-α. In conclusion, GW0742 may be a promising neurotherapeutic for the management of HI patients.

Topics: Animals; Blood Glucose; Cell Cycle Proteins; Cell Survival; Female; Glucose; Hypoxia; Inflammasomes; Inflammation; Ischemia; Male; MicroRNAs; Microscopy, Fluorescence; NLR Family, Pyrin Domain-Containing 3 Protein; Oxygen; PC12 Cells; Rats; Rats, Sprague-Dawley; Thiazoles

Pulmonary vascular diseases are increasingly recognised as important clinical conditions. Pulmonary hypertension associated with a range of aetiologies is difficult to treat and associated with progressive morbidity and mortality. Current therapies for pulmonary hypertension include phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, or prostacyclin mimetics. However, none of these provide a cure and the clinical benefits of these drugs individually decline over time. There is, therefore, an urgent need to identify new treatment strategies for pulmonary hypertension.. Here we show that the PPARbeta/delta agonist GW0742 induces vasorelaxation in systemic and pulmonary vessels. Using tissue from genetically modified mice, we show that the dilator effects of GW0742 are independent of the target receptor PPARbeta/delta or cell surface prostacyclin (IP) receptors. In aortic tissue, vascular relaxant effects of GW0742 were not associated with increases in cGMP, cAMP or hyperpolarisation, but were attributed to inhibition of RhoA activity. In a rat model of hypoxia-induced pulmonary hypertension, daily oral dosing of animals with GW0742 (30 mg/kg) for 3 weeks significantly reduced the associated right heart hypertrophy and right ventricular systolic pressure. GW0742 had no effect on vascular remodelling induced by hypoxia in this model.. These observations are the first to show a therapeutic benefit of 'PPARbeta/delta' agonists in experimental pulmonary arterial hypertension and provide pre-clinical evidence to favour clinical trials in man.

Topics: Administration, Oral; Animals; Cardiomegaly; Hypertension, Pulmonary; Hypoxia; Lung; Male; Mice; Mice, Transgenic; PPAR delta; PPAR-beta; Rats; Rats, Wistar; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; Thiazoles