The Peroxisome Proliferator-Activated Receptor ? Agonist Pioglitazone Protects Vascular Endothelial Function in Hypercholesterolemic Rats by Inhibiting Myeloperoxidase.

ABSTRACT: Objective:Hypercholesterolemia- (HC-) induced endothelial dysfunction is the first step of atherogenesis, and the peroxisome proliferator-activated receptor ? (PPAR? (PPAR? (PPAR?) has been reported to attenuate atherosclerosis formation; however, the underlying mechanisms are not fully understood. The present study was designed to determine whether myeloperoxidase (MPO) mediates HC-induced endothelial dysfunction and the role of the PPAR? agonist pioglitazone (PIO) in attenuating endothelial dysfunction. Methods:Male Wistar rats were fed with normal or high cholesterol diets for 8 weeks. HC rats were randomized to receive dapsone (DDS, the MPO inhibitor) during the last 6 days or PIO for the remaining 4 weeks. Vascular endothelial function was determined by comparing vasorelaxation to ACh, an endothelium-dependent vasodilator, and SNP, an endothelium-independent vasodilator in vascular rings in vitro. The vascular MPO activity, NO x content, and cGMP level were measured by the MPO activity assay kit, NO assay kit, and cGMP RIA kit. Results:Compared with rats fed with normal diet, endothelium-dependent vasodilation, NO x content, and cGMP level were decreased, and MPO activity was increased in thoracic aortas of rats fed with HC diet. There was a negative correlation between vascular endothelial function, NO x content or cGMP level, and MPO activity. PIO obviously reduced the MPO activity, increased NO x content and cGMP level, and improved endothelium-dependent vasodilation function in HC rats, which was essentially the same as that seen with DDS. And, there was a negative correlation between vascular endothelial function, NO x content or cGMP level, and MPO activity in the HC group and the PIO intervention group. Conclusion:MPO might provoke vascular endothelial dysfunction in hypercholesterolemic rats by reducing the NO biological activity and impairing the NO/cGMP/cGK signaling pathway. PIO might inhibit vascular MPO activity and increase NO bioavailability with the net result of reversing endothelial dysfunction.

SUBMITTER: Zhang D 

PROVIDER: S-EPMC7063881 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature