Atherosclerosis is the main underlying cause of heart disease. Atherosclerosis is an inflammatory disease that involves the arterial wall, and is characterized by the progressive accumulation of lipids and inflammatory cells within the intima of large arteries.
The complex pathophysiology of atherosclerotic disease is highlighted by the fact that many processes contribute to lesion development. Yet, it is well accepted that high serum levels of low-density lipoprotein cholesterol (LDL) play a main role in the initiation and progression of atherosclerosis. The continuous exposure of LDL particles induces endothelial activation/dysfunction which enhances the permeability of the endothelial layer and the expression of cytokines/chemokines and adhesion molecules.
Consequently, LDL particles infiltrate and accumulate in the extracellular matrix (ECM); circulating monocytes are then recruited and attach through the exposure of endothelial adhesion molecules. Once attached, they transmigrate into the subendothelial space where they transform into macrophages. All together this leads to the vascular secretion of chemotactic and growth factors which stimulate migration, accumulation and proliferation of vascular smooth muscle cells (VSMC) and leukocytes in the intimal layer, promoting plaque progression.
In fact, contractile VSMC change their phenotype to synthetic and migratory VSMC thereby invading the intima layer. In turn, LDLs retained in the ECM - mainly by proteoglycans - become targets for oxidative and enzymatic modifications. Oxidized LDLs (oxLDL) enhance a series of pro-inflammatory reactions via different mediators (TNF-alpha, IL-1, MCSF, etc), perpetuating the activation, recruitment and transmigration of monocytes and other inflammatory cells across the endothelial layer into the intima.
On the other hand, the attracted macrophages scavenge modified/oxidized LDLs, become lipid-laden, and convert into foam cells (Figure). In the early stages of atherosclerosis, the accumulation of foam cells evolves into fatty streak. Lesion complication occurs when foam cells release growth factors and cytokines, which further stimulate VSMC migration from the media into the intima where they divide and produce ECM components such as collagen, and contribute to the formation of a fibrous cap.
If the pathological triggering process persists and macrophages fail to remove accumulated cholesterol from the vessel, they become apoptotic, releasing cholesterol to the vessel wall and, more importantly, prothrombotic molecules (e.g., tissue factor) and metalloproteinases (enzymes able to digest the ECM scaffold).
Progression and complication of atherosclerotic plaques are also characterized by the formation of immature and leaky new vessels, making atherosclerotic lesions more prone to rupture (the so-called “vulnerable” plaques). Plaque disruption and the subsequent exposure of thrombogenic substrates initiates both platelet adhesion/activation and aggregation on the exposed vascular surface and the activation of the coagulation cascade, leading to thrombus formation (atherothrombosis) and the clinical manifestations of the atherosclerotic disease, acute myocardial infarction or sudden death (Figure).
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