COLL 133 |
| Thomas N. Tulenko, Dept Surgery, Thomas Jefferson University, 1025 Walnut St, Ste 605, Philadelphia, PA 19107, Gregory M. Troup, Drexel University, Philadelphia, PA 19104, and Steven P. Wrenn, Chemical Engineering Dept, Drexel University, 481 CAT Bldg, 3141 Chestnut Street, Philadelphia, PA 19104. |
| At least three types of cholesterol-rich membrane domains have been described in biological membranes including immiscible cholesterol monohydrate domains, cholesterol rafts and membrane caveolae. While clear biological functions have been ascribed to both rafts and caveolae, little attention has been directed to the biological consequences of cholesterol enrichment of cell membranes and the formation of cholesterol domains in vivo. Elevated blood cholesterol levels have been shown to result in the enrichment of the cell plasma membrane with cholesterol in arterial smooth muscle (SMC), endothelial cells (EC) and cardiac myocytes. In the early period of cholesterol feeding (within days), the cell membrane enriches with cholesterol and membrane fluidity decreases and in membrane bilayer width increases. This latter effect severely alters membrane protein function and thereby induces the modulation of vascular cells (SMC and EC) to the atherosclerotic phenotype. In cardiac myocytes, alterations in gene expression patterns lead to the development of a pre-clinical heart failure phenotype. A concentration-dependent effect of cholesterol on bilayer width has been confirmed in synthetic membranes using x-ray diffraction techniques. With time (weeks), phase separation of cholesterol in the membrane occurs, leading to the formation of immiscible cholesterol domains. Using a FRET assay, we estimate the lateral dimension of these domains to be nominally 20 nm. We believe that the formation of immiscible cholesterol domains initiates the genesis of crystalline cholesterol “clefts,” a hallmark of atherosclerotic lesions. Interestingly, the antihypertension drug, amlodipine restores the swollen “atherosclerotic membrane” to normal dimensions without altering membrane cholesterol content or membrane fluidity, and inhibits the development of atherosclerotic vascular disease independent of blood pressure lowering in humans. These data support the concept that elevated blood cholesterol levels enrich the cell membrane in cardiovascular cells, expands bilayer structure and induces the formation of immiscible cholesterol domains. Together these membrane alterations constitute a “membrane lesion” that contributes to the pathogenesis of major human diseases including coronary artery disease, stroke and heart failure. |
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Bio-Colloids
2:00 PM-4:30 PM, Monday, March 29, 2004 Marriott -- Grand Ballroom K, Oral
Division of Colloid and Surface Chemistry |