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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

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

Zhang Dapeng D Wang Yehong Y Yi Ming M Zhang Suli S Wu Ye Y

Cardiology research and practice 20200107

<h4>Objective</h4>Hypercholesterolemia- (HC-) induced endothelial dysfunction is the first step of atherogenesis, and the peroxisome proliferator-activated receptor γ (PPARγ (PPARγ (PPARγ) 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 PPARγ agonist piogl ...[more]

PMID: 32190383

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Project description:Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone modulates inflammation through PPARalpha mechanisms.The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARgamma agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPARalpha but not PPARgamma agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARalpha activation, we studied pioglitazone's effects via PPARalpha.Pioglitazone effects on known PPARalpha responses--ligand binding domain activation and PPARalpha target gene expression--were tested in vitro and in vivo, including in wild-type and PPARalpha-deficient cells and mice, and compared with the effects of other PPARgamma (rosiglitazone) and PPARalpha (WY14643) agonists.Pioglitazone repressed endothelial TNFalpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IkappaBalpha in a manner dependent on both pioglitazone exposure and PPARalpha expression. Pioglitazone also activated the PPARalpha ligand binding domain and induced PPARalpha target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IkappaBalpha expression in wild-type but not PPARalpha-deficient mice.Pioglitazone regulates inflammatory target genes in hepatic (IkappaBalpha) and endothelial (VCAM-1) settings in a PPARalpha-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.

Dataset Information

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

Publications

The Peroxisome Proliferator-Activated Receptor <i>γ</i> Agonist Pioglitazone Protects Vascular Endothelial Function in Hypercholesterolemic Rats by Inhibiting Myeloperoxidase.

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