Laboratory: Lipoproteins and Atherosclerosis

PREVIOUS PROJECTS

Transcytosis of macromolecules through • the vascular endothelium (Vasile E. et al., J Cell Biol, 1983).
Original model of atherosclerosis, the • hyperlipemic hamster (Nistor A. et al., Atherosclerosis, 1987).
Pathobiochemical events occurring at the • inception of atherosclerosis: prelesional stage (Simionescu N. et al., Am J Pathol., 1986).
Lesional stages of atherosclerosis (• Sima A. et al., J Submicrosc Cytol Pathol, 1990).
Human atheroma: identification of oxi• dized and glycated LDL (Sima A. and Stancu C., J Cell Mol Med, 2002).
Macroangiopathy, studies in an original • model “the simultaneously hyperlipidemic-diabetic (HD) hamster” (Simionescu M. et al., Am J Pathol, 1996)
Gene polymorphism of apolipoprotein E • and apolipoprotein A-V – risk factors for subjects with metabolic syndrome; impact of obesity in the generation of diabetes and cardiovascular diseases in urban communities from Romania (Sima A. et al., Clin Chem Lab Med, 2007, Niculescu L. et al., Clin Chem Lab Med, 2007).
Effect of irreversibly glycated LDL on hu• man endothelial and vascular smooth muscle cells (Toma L. et al., Biochem Biophys Res Commun, 2009, Sima A.V. et al., J Cell Mol Med, 2010).
Tentatives to arrest or revert cardiovascular • diseases (Toma L. et al., Biochem Biophys Res Commun, 2011).

CURRENT PROJECTS

New predictive biomarkers for the evolution of the stable or unstable coronary artery disease

The goal of this project is to establish new biomarkers with potential to predict the risk for developing life-threatening events in coronary artery diseased (CAD) patients and to test the relevance of the measured biomarkers in patients by correlating them with the clinical evolution of CAD.
The novelty of the project is the detection of oxidized lipid molecules, translational regulatory molecules (miRNAs) and inflammatory molecules, the establishment of a link between the effect of oxidized lipids on the cellular secretion of miRNAs, pro-inflammatory molecules and on the switch of monocytes to the inflammatory phenotype (using cultured human endothelial cells and monocytes), and the correlation between circulating endothelial progenitor cells and the inflammatory monocytes from the CAD patients blood.
The originality of the project resides in the final design of a protocol using a group of biomarkers implicated in the three pathways of atherosclerosis (lipid oxidation, transcriptional regulation and inflammation) that have the potential to predict CAD evolution and the transfer of the methodology for detection of the new biomarkers from bench to the clinic, to allow, at reasonable cost, the early prediction of life-threatening events, which will lead to a prolongation of the lifespan.
The objectives are: (i) identification of putative biomarkers with prognostic value in the blood of patients with stable angina, unstable angina or myocardial infarction: oxidized lipids and dysfunctional lipoproteins; (ii) identification of circulating miRNAs and inflammatory molecules in the blood of patients with stable angina, unstable angina or myocardial infarction; (iii) setting up of an in vitro experimental model to evaluate the effect of CAD patients sera on the production of the inflammatory biomarkers by cultured endothelial cells and macrophages; evaluation of circulating endothelial progenitor cells and monocytes (Fig. 1).



Fig. 1. Schematic representation of the working hypothesis. The project proposes to validate new biomarkers with predictive potential for the evolution of CAD by following three distinct pathways. In hyperlipidemia related CAD, phospholipids and fatty acids from circulating lipoproteins suffer oxidative modifications generating reactive species such as HPETE, HPODE, or 4-HDDE which we propose as predictive biomarkers for the evolution of stable and unstable angina. These aggressive oxidized lipids may induce an inflammatory response in the cells of the arterial wall (i.e. endothelial cells) or circulating inflammatory cells (monocytes).



Fig. 2. a) The structure and composition of LDL particle; b) the lipid substrates and products of 12/15-lipoxygenases (LPOX); c) the working hypothesis illustrating the questions that the project aims.