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Antiatherogenic helical segments of apo A-I

Institution: Lawrence Berkeley National Laboratory
Investigator(s): John Bielicki, Ph.D.
Award Cycle: 2004 (Cycle 13) Grant #: 13IT-0025 Award: $141,230
Subject Area: Cardiovascular Disease
Award Type: Inno Dev & Exp Awards (IDEAS)
Abstracts

Initial Award Abstract
Atherosclerosis is a common form of heart disease that has a high prevalence in people that use tobacco products including those that smoke cigarettes. Elevated levels of HDL-cholesterol, i.e. the “good” cholesterol, normally protect against atherosclerosis, but exposure to cigarette smoke produces HDL deficiency and, with it, an increased risk of atherosclerotic heart disease. The protective effect of HDL is related, in part, to its ability to extract cholesterol from cells of the artery wall and to transport cholesterol back to the liver for its release from the body. This process is known as “reverse cholesterol transport”. Exposure to cigarette smoke facilitates the deposition of “bad” cholesterol into cells of the artery wall overwhelming the protective capacity of HDL, which is low in smokers. This imbalance, which favors cholesterol deposition in arteries at the expense of its removal, occurs over decades of tobacco use.

Recent advances in our understanding of HDL structure and function suggest new strategies for the treatment of tobacco-related diseases such as atherosclerosis. The major protein of HDL is apolipoproteinA-I (apoA-I). ApolipoproteinA-I mediates the removal of excess cholesterol from macrophage foam cells within the artery wall. This process of cellular cholesterol efflux mediated by apoA-I is responsible for the protective effects attributed to HDL. ApoA-I mediated cholesterol efflux requires a partner in the form of a molecular “pump” known as ABCA1 that facilitates cholesterol release from cells of the artery wall. Understanding the nature of the interaction between apoA-I and the ABCA1 transporter is of great clinical interest allowing the development of new therapeutic strategies for reversing atherosclerotic lesions. We have tentatively identified the structural basis for the interaction between apoA-I and the ABCA1 transporter. Our studies suggest that a discrete structural element present in apoA-I is responsible for extracting cholesterol from cells via the ABCA1 transporter. Moreover, this apoA-I structural element appears also to prevent the cellular degradation of ABCA1 providing a means for up-regulating the HDL biosynthetic machinery. In this regard, the structural element that we have identified appears to selectively mediate cholesterol efflux through the ABCA1 pathway. These findings are truly exciting suggesting that a small peptide based on the apoA-I structural element that stimulates ABCA1-dependent cholesterol efflux may have practical clinical applications as a therapeutic agent to combat cigarette smoke-induced atherosclerosis.