- Project on Cholesteryl Hemiesters and Dysfunctional Lysosomes in Atherosclerosis
Atherosclerosis, a chronic systemic inflammatory disease that leads to myocardial infarction, stroke, and lower limb ischemia, is the major cause of cardiovascular disease (CVD)-related death globally. It results from constitutive uptake by macrophages and smooth muscle cells of modified Low Density Lipoproteins (LDL), trapped in the arterial intima that, with time, start to accumulate irreversibly in lysosomes, contributing to chronic inflammation, cell death etc.
One of the modifications that LDL undergoes is lipid oxidation, which leads to the formation of oxidized lipid species that, with time, will be detected in the blood. Based on this reasoning, we determined the lipidome of the blood plasma of CVD patients. The results showed that while total cholesterol concentrations were only slightly different, the concentrations of a family of previously not investigated oxidized-lipids, cholesteryl hemiesters (ChE), was significantly higher in CVD patients than in normal donors.
Lysosomal dysfunction is a common and early contributing factor in the onset of several chronic diseases but it has been almost neglected in the pathobiology of atherosclerosis.
Thus, the goal of this project is to characterize the novel family of oxidized lipids as new risk factors in atherosclerosis and as inducers of lysosome dysfunction as well as to understand the molecular mechanisms behind lysosomal dysfunction in ChE-treated macrophages, smooth muscle cells and in zebrafish larvae.
We are using cutting-edge techniques such as shotgun lipidomics alongside complementary molecular cell biology methods. We are confident that this proposal will uncover important new CVD risk factors and concepts underlying the pathogenesis of atherosclerosis that may guide the development of new drugs with therapeutic activity towards CVD.