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Step One- Small, Dense LDL Enters the Intimal Space
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Lp-PLA2 is an enzyme which circulates primarily in association with LDL and is believed to have a causal role in atherosclerosis.
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Initially, small, dense LDL within the lumen may penetrate into the interstitial spaces between endothelial cells lining the artery and infiltrate into the intimal space. |
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Once within the intima, LDL may be oxidized. Upon oxidation, LDL becomes a viable substrate for the Lp-PLA2 enzyme. |
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Step Two- Oxidized LDL is Catalyzed by Lp-PLA2 Enzyme
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Phosphatidylcholines within oxidized LDL are hydrolyzed by Lp-PLA2, releasing two pro-inflammatory mediators, lysophosphatidylcholine (lyso-PC) and oxidized fatty acid (OxFA). |
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Lyso-PC and OxFA are pro-inflammatory mediators that stimulate the production of adhesion molecules and cytokines, thus initiating the vascular inflammatory response associated with atherosclerosis. |
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Step Three- Inflammatory Response and Plaque Formation
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Adhesion molecules binding to the arterial wall and cytokine production attracts Monocytes to the intimal space where they differentiate into activated Macrophages. |
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Macrophages engulf the oxidized LDL, eventually transforming into Foam Cells. Additionally, macrophages associated with atherosclerotic plaque formation also produce more Lp-PLA2. |
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Foam Cells aggregate to form Atherosclerotic Plaque. |
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Atherosclerotic Plaque promotes endothelial compromise by producing cytokines and proteases that degrade the fibrous cap enclosing the necrotic lipid core of the plaque. |
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The plaque weakens and ruptures, leading to formation of a thrombotic clot, and potentially a coronary event or stroke. |
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