Abstract
Background: Endotheliotoxic hyperlipidemia provide impaired eNOS derived NO production, excessive free-radicals, adhesive molecule generation, vascular lipid accumulation, atherosclerosis development & progression. NO replacement by NO donors can restore NO deficit. HDLs have anti-atherogenic properties and are carriers of excessive cellular cholesterol via reverse cholesterol transport (RCT) pathway. Lipoprotein enrichment by anionic phosphatidylinositol (PI) increases the negative surface potential of lipoproteins and stimulate RCT. PI stimulates rapid flux and clearance of plasma choles-l by increased hepatic uptake. Objective: Regression of atherosclerosis stimulating RCT with experimental combination of NO donor in PI nanocapsules (AlphaX1). Methods: 30 rabbits fed with 2%cholesterol diet for 6 months After 6 m subdivided in 3 groups. G1-10 without treatment. G2-treated with AlphaX1 for 10 days, G3-treated for 20 days. 5 rabbits-control. Animals sacrificed after 10 and 20 days of treatment. Abdominal aorta, part snap frozen in cryostat-OilRedO staining, part exposed for morphology and electron microscopy. Results: Morphology (x100-x27000): G1-numerous vacuoles with neutral lipids and foam cells under endothelium, proliferation of solitary smooth muscle cells containing lipid vacuoles; G2-moderate deposition of lipid vacuoles & foam cells in sub-endothelium, restoration of endothelium. G3-express reduction of lipid vacuoles & foam cells, restoration of elastic fibers, regeneration of endothelium.OilRedO, C 1.4±0.2% G1 38.2±3.6%. G2 7.3±0.8%, G3 2.3±0.6%. Conclusion: Data shows evidence that AlphaX1 provide regeneration of endothelial cells, restoration of elastic fibers (probably due to regulation of fibulin5 by PI3K/Akt), anti-inflammatory effect, clearance of foam cells from neutral lipids and regression of atherosclerosis. AlphaX1 provide antiatherogenic properties of NO and PI, probably by reduction in cytokines production, decrease in adhesion molecules expression, monocyte-endothelium adhesion inhibition, increased cholesterol efflux and plasma clearance via hepatic uptake. AlphaX1 could be a potential new therapeutic agent for prophylaxis & treatment of hyperlipidemia and atherosclerosis.
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