Oxidation and Reactive Carbonyl Resistant Apolipoprotein A-I (ApoA-I)
Principal Investigator: Jay Heinecke
Apolipoprotein A-I (ApoA-I) is the major protein component of high density lipoprotein (HDL) in plasma. ApoA-I protects against atherosclerosis by removing excess cholesterol from arterial macrophages, reducing inflammation, and inhibiting lipoprotein oxidation. A proprietary formulation of wild type human ApoA-I in the form of reconstituted HDL is currently in clinical trials and shows promising preliminary data as a novel therapeutic for atherosclerosis. One current obstacle in the field is that ApoA-I is susceptible to oxidative damage that inhibits its cholesterol efflux capacity. This activity is particularly prevalent in the atherosclerotic plaque of individuals with cardiovascular disease.
This technology is an engineered recombinant ApoA-I protein that modifies several key amino acid residues that are at the primary sites of oxidative damage. These modifications prevent the oxidation of key residues that would normally lead to the inhibition of ApoA-I’s lipid efflux and signaling capabilities. The minimally modified ApoA-I is not only oxidative and carbonyl resistant, but also retains wild-type cholesterol efflux capacity.
According to the WHO, cardiovascular and atherosclerotic diseases represent the leading cause of mortality in developed nations. Drugs currently available are effective for preventing the development plaque, but are less effective at actually decreasing the existing plaque burden. HDL-targeted therapies are emerging as an important new class of pharmaceuticals, which for the first time may reduce existing plaque deposits by elevating HDL and reverse cholesterol transport. The therapeutic potential of apoA-I has been recently assessed in patients with acute coronary syndromes, using a recombinant form of a naturally occurring variant of apoA-I (called apoA-I Milano). An oxidation resistant form of apoA-I, used alone or in conjunction with other forms of apoA-1, could represent an improved treatment for the prevention and reversal of cardiovascular disease.
For more info, contact: Dennis Hanson
- Baohai Shao, Michael N. Oda, Constanze Bergt, Xiaoyun Fu, Pattie S. Green, Nathan Brot, John F. Oram, Jay W. Heinecke (2/22/2006), Myeloperoxidase Impairs ABCA1-dependent Cholesterol Efflux through Methionine Oxidation and Site-specific Tyrosine Chlorination of Apolipoprotein A-I, Journal of Biological Chemistry, 9001 - 9004
- Shao B, Pennathur S, Heinecke JW (2/24/2012), Myeloperoxidase targets apolipoprotein A-I, the major high density lipoprotein protein, for site-specific oxidation in human atherosclerotic lesions., J Biol Chem.
- Shao B, Oda MN, Oram JF, Heinecke JW (July 2006), Myeloperoxidase: an inflammatory enzyme for generating dysfunctional high density lipoprotein., Curr Opin Cardiol.
- Baohai Shao, Chongren Tang, Jay W. Heinecke, John F. Oram (July 2010), Oxidation of apolipoprotein A-I by myeloperoxidase impairs the initial interactions with ABCA1 required for signaling and cholesterol export, J Lipid Res., 1849 - 1858
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