Lysosomes, acidic, hydrolase-rich cellular organelles, are the final destination of endocytic and autophagic pathways. Cell homeostasis is vitally linked to lysosomal function; malfunction being associated with several chronic pathologies including atherosclerosis, the main cause of cardiovascular diseases. Lysosomes are involved in almost the whole process of atherosclerosis. We aim to contribute to the better understanding of these pivotal organelles in the biology/physiology and pathophysiology of atherosclerosis.
We expect to:
Our research currently applies some state-of-the-art techniques including Live-Cell Imaging, EM, Shotgun Lipidomics, Biochemical, Biophysical, and Pharmacological approaches applied to primary human cells, animal models and human tissues.
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.
Research carried out by several of our laboratories is supported by the LYSOCIL project and has been published in Traffic magazine.
The final conference of the LYSOCIL project took place on the 8th and 9th of April at the Hotel Vila Galé in Cascais. It featured presentations from the various project partners and collaborators worldwide, including Italy and Germany.
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