Abstract
Objective 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 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, NOx 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, NOx 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, NOx content or cGMP level, and MPO activity. PIO obviously reduced the MPO activity, increased NOx 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, NOx 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.
Highlights
Coronary artery disease (CAD) becomes one of the most important diseases that affect longevity and survival quality of aging [1]
Endothelial dysfunction is the first stage in the progression of atherogenesis [2], and hypercholesterolemia is one of the most important causes of endothelial dysfunction [3]. e mechanism of vascular endothelial dysfunction caused by hypercholesterolemia is complex, in which a decrease in the bioavailability of nitric oxide (NO) [4] and impaired NO/cGMP/cGK signaling are considered important contributory mechanisms [5]. erefore, if the Cardiology Research and Practice cause responsible for decreased NO bioavailability in hypercholesterolemia is determined and blocked, it is thought that vascular endothelial function could be effectively maintained, thereby reducing the occurrence of atherosclerosis
After administration of acetylcholine (ACh) across a dose-dependent concentration gradient of 10− 9–10− 5 mol/L, the concentration-dependent vasodilatory response was seen in the thoracic aorta rings of normal diet rats (Figure 1(a)). e concentration-dependent curve induced by ACh in the thoracic aorta rings of hypercholesterolemic rats was severely shifted to the right, and the log EC50 of the vascular tone increased from − 7.29 ± 0.16 mol/L to − 6.61 ± 0.27 mol/L as compared with the normal control group (P < 0.01; Figure 1(c)). e maximum vasodilatation decreased from 97.88 ± 9.53% to 50.51 ± 2.44% (P < 0.01; Figures 1(b) and 1(d))
Summary
Coronary artery disease (CAD) becomes one of the most important diseases that affect longevity and survival quality of aging [1]. Endothelial dysfunction is the first stage in the progression of atherogenesis [2], and hypercholesterolemia is one of the most important causes of endothelial dysfunction [3]. E mechanism of vascular endothelial dysfunction caused by hypercholesterolemia is complex, in which a decrease in the bioavailability of nitric oxide (NO) [4] and impaired NO/cGMP/cGK signaling are considered important contributory mechanisms [5]. Erefore, if the Cardiology Research and Practice cause responsible for decreased NO bioavailability in hypercholesterolemia is determined and blocked, it is thought that vascular endothelial function could be effectively maintained, thereby reducing the occurrence of atherosclerosis. Studies have shown [8] that MPO is abundantly accumulated in the basement membrane under the vascular endothelium in hypercholesterolemia, and it is speculated that it may lead to endothelial dysfunction by the precipitation of NO. The specific mechanism of action of MPO remains to be elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
