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Animal models of human metabolic syndrome and pathological angiogenesis

Łukasz Wątor 1Urszula Raźny 1Anna Polus 1Jerzy Stachura 2Grzegorz Dyduch 2Yvonne Wan 3Hans G. Joost 4Aldona Dembińska-Kieć 1

1. Jagiellonian University Collegium Medicum Department of Clinical Biochemistry, Kopernika 15 a, Kraków 31-501, Poland
2. Jagiellonian University, Medical School, Department of Pathology, Grzegórzecka 16, Kraków 31-531, Poland
3. Harbor-University of California at Los Angeles Medical Center, Torrance, CA 90502, United States
4. German Institute of Human Nutrition (DIFE), Potsdam 14558, Germany

Abstract

Introduction: Obesity, insulin intolerance, hypertension, dyslipidaemia and hyperleptinaemia are the main clinical symptoms of metabolic syndrome leading to vascular injury, atherosclerosis, diabetes and pathological angiogenesis.

Aim of the study was to define the possible link between metabolic syndrome biochemical parameters and angiogenesis.

Methods: Three animal models with different metabolic dysfunction were used in the study: hepatocyte RXRalpha deficient mice (hyperleptynaemia, hypercholesterolaemia), NZO and backcross NZO/F1(NZOxSJL) mice (obesity, insulin resistance, hyperleptinaemia). Mice were fed with standard or the high fat diet for seven weeks. Body weight, serum glucose, triglycerides, cholesterol, insulin, leptin and adiponectin were monitored. Angiogenesis was measured in subcutaneously implanted matrigel with 25 nM bFGF during the last week of study. The angiogenic response was assessed by a number of CD31 positive structures. Gene expression in matrigel plug cells was analysed by microarray (Mouse 430A_2, Affymetrix, 14 000 genes).

Results: High fat diet increased leptin and cholesterol concentrations in the liver RXRalpha deficient mice. The tendency to decrease number of vessels with lumen was also observed in these animals fed with high fat diet and number of CD31 positive cells was correlated positively with the blood glucose and insulin. In microarray activation of insulin receptor pathway, glucose transporters, glycolysis enzymes, fatty acid syntetase, transcription factors related to adipocytes differentiation was observed. This may argue for promoting adipogenesis in the angiogenesis region.

High fat diet elevated body weight, serum concentration of glucose, cholesterol, insulin and leptin in NZO and NZO/F1 mice. The high fat diet raised number of CD 31 positive capillaries, what was positively correlated with glucose level. Analysis of gene expression for NZO model showed upregulation of genes related to cytoskeleton remodeling, endothelial cell migration as well as activation of proangiogenic growth factors.

Conclusions: High fat diet caused different effect in animal models of metabolic syndrome, leading to decrease of angiogenesis in hepatocyte RXRalpha deficient mice and increase of angiogenesis in obese and insulin resistant (NZO, NZO/F1) ones. The glucose /insulin , but not proangiogenic leptin/adiponectin concentrations might be predictive for angiogenic response.

Project supported by Polish Committee of Science Grant No: PBZ-MIN-005/P04/2002/5

 

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Related papers

Presentation: Poster at Zjazd Polskiego Towarzystwa Biochemicznego, Sympozjum G, by Łukasz Wątor
See On-line Journal of Zjazd Polskiego Towarzystwa Biochemicznego

Submitted: 2007-05-07 17:53
Revised:   2009-06-07 00:44