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Jan 27, 2014

Shadowing Good Cholesterol While It Walks the Dark Side

  • Good cholesterol, or high-density lipoprotein (HDL), doesn’t always live up to its reputation. Instead, it sometimes runs with the wrong crowd, turns awry, and loses its cardioprotective properties. Good cholesterol can even become harmful, promoting inflammation and atherosclerosis.

    The bad influence on good cholesterol is myeloperoxidase (MPO). As indicated by recent studies, MPO can oxidize good cholesterol’s major structural protein, apolipoprotein A1 (apoA1). Specifically, the studies show that in vitro oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function.

    Determined to uncover additional details, a group of researchers at the Cleveland Clinic decided to investigate the structural details of dysfunctional apoA1. Not only did they learn which part of apoA1 goes awry, they gathered clues about apoA1’s subsequent disease-promoting ways.

    The researchers were led by Stanley Hazen, M.D., Ph.D., vice chair of translational research for the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart and Vascular Institute at Cleveland Clinic. “Identifying the structure of dysfunctional apoA1 and the process by which it becomes disease-promoting instead of disease-preventing is the first step in creating new tests and treatments for cardiovascular disease,” said Dr. Hazen.

    Dr. Hazen and his colleagues used phage display affinity maturation to develop a method for identifying dysfunctional apoA1/HDL. (In particular, they generated a high-affinity monoclonal antibody that specifically recognizes both apoA1 and HDL that have been modified by the MPO-H2O2-Cl system.) In addition, they discovered the process by which it is oxidized and turned dysfunctional in the artery wall. Finally, they then tested the blood of 627 Cleveland Clinic cardiology patients for the dysfunctional HDL and found that higher levels raised the patient's risk for cardiovascular disease.

    Dr. Hazen’s team published its results January 26 in Nature Medicine, in an article entitled “An abundant dysfunctional apolipoprotein A1 in human atheroma.” In this article, the authors wrote, “An oxindolyl alanine (2-OH-Trp) moiety at Trp72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirmed a critical role for apoA1 Trp72 in MPO-mediated inhibition of the ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo.”

    In other words, apoA1 loses its ability to transfer cholesterol out of the artery wall and deliver it to the liver, from which cholesterol is excreted. Instead, a large proportion of apo1 in the artery wall becomes oxidized during atherosclerosis.

    According to the researchers, “ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation but accounts for 20% of the apoA1 in atherosclerosis-laden arteries. OxTrp72-apoA1 recovered from human atheroma or plasma is lipid poor [and] virtually devoid of cholesterol acceptor activity. Moreover, the researchers found that the modified apoA1 demonstrated both a potent proinflammatory activity on endothelial cells and an impaired HDL biogenesis activity in vivo.”

    Reflecting on the significance of these results, Dr. Hazen said, “Now that we know what this dysfunctional protein looks like, we are developing a clinical test to measure its levels in the bloodstream, which will be a valuable tool for both assessing cardiovascular disease risk in patients and for guiding development of HDL-targeted therapies to prevent disease.” The research also points toward new therapeutic targets for pharmaceuticals, such as those designed to prevent the formation of dysfunctional HDL and the development or progression of atherosclerosis.



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