Effect of 3-hydroxymethylglutaryl CoA reductase of inhibitors on ATP-binding cassette transporter-1 protein (ABCA-1) in uremic serum stimulated endothelial cells

• Grant number: 14/00042-8
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): June 01, 2014
• Effective date (End): May 31, 2016
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Marcelo Costa Batista
• Grantee: Silmara de Melo Carmona
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Atherosclerosis, the pathological basis of dyslipidemia, is closely associated with the occurrence of Cardiovascular Disease (CVD). CVD is highly prevalent in Chronic Kidney Disease (CKD) and is a major cause of mortality in patients with CKD. It involves metabolic abnormalities such as hypercholesterolemia, metabolic acidosis, insulin resistance, accumulation of cytokines and endothelial dysfunction. The endothelium presents endocrine and exocrine function and its exposure to the uremic environment may cause dysfunction, contributing to the exacerbation of hypercholesterolemia increasing the risk of atherosclerosis development, thus the mechanism related to Reverse Cholesterol Transport (RCT) that occurs from peripheral cells to the liver by HDL molecule, plays a key role in the protection of the vascular bed, preventing transmigration, the formation of foam cells and accumulation of thrombogenic material. An important component of the RCT is a 264 kDa cytoplasmic protein denominated ATP-binding cassette transporter-1 (ABCA-1) mapped on chromosome 9q3 and its transcription can be activated by products from intracellular metabolism of cholesterol, which bind to receptors liver X receptor (LXR) and retinoic X receptor (RxR), forming dimers required in transcriptional promoter activation. Currently, the statins have been used primarily for the treatment of dyslipidemia, its act by inhibiting the enzyme 3-hydroxymethylglutaryl CoA reductase, preventing the formation of mevalonic acid and its precursors. The pleiotropic effects of statins are not yet fully elucidated, and no evidences support that its use has beneficial effects on attenuation of cardiovascular outcome or its potential effects on the modulation of the ABCA-1 transporter in CKD patients. This aim of this project is to assess whether the action pleiotropic of statin has beneficial effect on vascular protection, by exposition of vein endothelial cells from human umbilical cord to the uremic environment, and investigate potential alterations in ABCA-1 transporter transcription gene. (AU)