P480Antiatherogenic effect of quercetin is mediated by proteasome inhibition in the aorta and circulating leukocytes.

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Abstract

Proteasomal degradation of proteins contributes significantly to the regulation of the vital functions of cells. Disturbances in proteasomal proteolysis play pivotal role in pathologies of the cardiovascular system, such as atherosclerosis. Here, we report data showing the angioprotective properties of quercetin mediated by its effect on proteasomal proteolysis.

Methods: Experiments were performed on 56 rabbits which divided on the next groups: control, cholesterol-rich diet and quercetin application with cholesterol-rich diet. Monocytes, lymphocytes and PMN were fractionated by centrifugation on a Percoll gradient and activities of proteasome were determined using fluorogenic substrates. The aorta and vena cava posterior was homogenized and used for biochemical analyses. The levels of cholesterol, triglyceride, LDL, and VLDL were determined using Bio System A25. Histological changes in aortic tissues were established using Oil Red and hematoxylin staining.

Results: Our data clearly indicate the adequacy of our model, showing the increase of cholesterol, triglycerides, LDL and VLDL levels up to 32-, 2.2-, 30-, and 5-fold, respectively. We show proteasomal trypsin-like (TL) activity increased up to 2.4-fold, chymotrypsin-like (CTL) activity increased by up to 43% and peptidyl-glutamyl peptide-hydrolyzing (PGPH) activity increased by up to 10% after 8 weeks of a cholesterol-rich diet. Administration of quercetin (Quertin) to animals following a cholesterol-rich diet significantly decreased all types of proteolytic proteasome activities both in tissues and in circulating leukocytes and was associated with the reduction of atherosclerotic lesion areas in the aorta. Application of quercetin have not influence on lipids level. Also, Quercetin (Quertin) significantly decreased proteasomal TL activity 1.85-fold in monocytes, and decreased the CTL and PGPH activities more than 2-fold in polymorphonuclear leukocytes. Application of quercetin decrease proteasomal activity in aorta, in venous tissues activity of proteasome have not significantly changes in cholesterol-rich diet.

Conclusions: These data indicate that the increase of proteasome activity in aorta and blood cells plays a pathogenic role during the development of atherosclerosis. Increase of proteasome activity was shown only in aortic tissues, not in venous tissiues (resistent to atherogenic factors) in CRD. Antiatherogenic action of quercetin is due to its inhibitory effect on proteasome activity.

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