title: Arterial retention of remnant lipoproteins ex vivo is increased in insulin resistance because of increased arterial biglycan and production of cholesterol-rich atherogenic particles that can be improved by ezetimibe in the JCR:LA-cp rat.
abstract: BACKGROUND
  Literature supports the "response-to-retention" hypothesis-that during insulin resistance, impaired metabolism of remnant lipoproteins can contribute to accelerated cardiovascular disease progression. We used the JCR:LA-cp rat model of metabolic syndrome (MetS) to determine the extent of arterial accumulation of intestinal-derived remnants ex vivo and potential mechanisms that contribute to exacerbated cholesterol deposition in insulin resistance.
  
  
  RESULTS
  Arteries from control and MetS (insulin-resistant) JCR:LA-cp rats were perfused ex vivo with Cy5-labeled remnant lipoproteins, and their arterial retention was quantified by confocal microscopy. Arterial proteoglycans were isolated from control and MetS rats at 6, 12, and 32 weeks of age. There was a significant increase in the arterial retention of remnants and in associated cholesterol accumulation in MetS rats as compared to control rats. Mechanistic studies reveal that increased cholesterol deposition is a result of greater arterial biglycan content; longer glycosaminoglycans and increased production of cholesterol-rich intestinal-derived remnants, as compared to controls. Additionally, perfusion of vessels treated with ezetimibe, alone or in combination with simvastatin, with remnants isolated from the respective treatment group reduced ex vivo arterial retention of remnant-derived cholesterol ex vivo as compared to untreated controls.
  
  
  CONCLUSIONS
  Increased progression of atherosclerotic cardiovascular disease in MetS and type 2 diabetes mellitus might be explained in part by an increase in the arterial retention of cholesterol-rich remnants. Furthermore, ezetimibe alone or in combination treatment with simvastatin could be beneficial in ameliorating atherosclerotic cardiovascular disease in insulin resistance and MetS.
authors: Metabolic and Cardiovascular Diseases Laboratory, University of Alberta, Edmonton, Alberta, Canada.
authors: Rabban
authors: R
authors: Mangat
authors: Samantha
authors: S
authors: Warnakula
authors: Faye
authors: F
authors: Borthwick
authors: Zahra
authors: Z
authors: Hassanali
authors: Richard R E
authors: RR
authors: Uwiera
authors: James C
authors: JC
authors: Russell
authors: Christopher I
authors: CI
authors: Cheeseman
authors: Donna F
authors: DF
authors: Vine
authors: Spencer D
authors: SD
authors: Proctor
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001158:Arteries / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy / Q000503:physiopathology*; D001384:Azetidines / Q000627:therapeutic use*; D058578:Biglycan / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe; D007333:Insulin Resistance / Q000502:physiology*; D008074:Lipoproteins / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000503:physiopathology*; D051381:Rats; D019821:Simvastatin / Q000627:therapeutic use
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D058578:Biglycan; D008074:Lipoproteins; D002784:Cholesterol; D019821:Simvastatin; D000069438:Ezetimibe
keywords: arterial remodeling; biglycan; metabolic syndrome; triglyceride-rich remnant lipoproteins