|Ph.D Student||Cohen Elad|
|Subject||Crosstalk among the Human Carotid Athersclerotic Plaque|
Constituents, and Blood Lipoproteins and
|Department||Department of Medicine||Supervisors||Professor Emeritus Michael Aviram|
|Professor Jacob Vaya|
|Full Thesis text|
Background: Atherosclerosis is a chronic disease of the arterial wall which characterized by accumulation within the intima of the arterial wall of lipids and oxidized lipids, cells derived from the circulation (e.g., monocytes and T cells) and from the artery itself (e.g., endothelial and smooth muscle cells), inflammatory factors such as cytokines and chemokines, as well as proteins that are excreted from cells or in association with necrotic cell debris. During plaque formation, endothelial cells dysfunction resulted in enhanced permeability of the artery wall. Consequently, plaque components are in direct contact with circulating blood elements and thus they could affect each other.
Aim: our ongoing research is focused on the mutual interaction between the human carotid plaque components, and elements in the circulating blood, in order to better understand their involvement and their ability to alter atherosclerosis progression rate.
Results: This study shows that human plaque contains pro-atherogenic as well as anti atherogenic compounds. It contains hydroperoxide of linoleic acid (LA-13OOH) which is more abundance in symptomatic than asymptomatic patients. Moreover plaque LA-13OOH is inversely correlates with serum HDL and PON1 activity, and directly correlates with serum HbA1c. In addition, Protein(s) of the plaque affect HDL protein composition by releasing its major protein- apolipoprotein A1 (Apo A1), increasing HDL particles diameter and therefore, impairing its anti-oxidant activity. Such protein(s) can accelerates plaque formation since HDL anti-oxidant activity has a central role in atherosclerosis progression. On the other hand, the human carotid plaque contains protein(s) that decrease cholesterol biosynthesis rate in macrophages through HMGCoA R regulation. Such protein(s) may protect the macrophages by reducing cholesterol accumulation and delay foam cell formation. In addition, the human carotid plaques contain specific phosphatidylcholin (PC) that binds paraoxonase 1 (PON1) in its HDL binding site, increases its activity and enhances its uptake by macrophage at the expense of its binding to HDL. This scenario can be a useful mechanism for macrophage defense, as PON1 protects macrophage from oxidative stress and from plaque Triglyceride damage, decreases macrophage cholesterol biosynthesis and affect macrophage protein expression.
Conclusions: the human carotid plaque is a living tissue, being in constant contact with elements in the circulation such as macrophages, HDL and LDL, affects them and affected by them. Plaque composed from atherogenic compounds that accelerate its progression but also contains anti-atherogenic elements which can delay plaque progression by protecting macrophages- the major player in plaque formation- from the pro-atherogenic environments of the plaque. The balance among these pro/anti-atherogenic agents and the network produced by their interactions, probably determine the rate of plaque development and atherosclerosis progression.