Oxidized, Dysfunctional HDL Evident in Atheroma

January 27, 2014

CLEVELAND, OH — In the latest twist on the complicated nature of HDL cholesterol, researchers have published a study this week showing that when oxidized at a specific site on apolipoprotein A1 (apoA1), HDL cholesterol becomes dysfunctional and proinflammatory[1]. Importantly, the group also found that this dysfunctional apoA1 accounts for 20% of apoA1 in arteries diseased with atherosclerosis.

In the study, published online January 26, 2014 in Nature Medicine, Dr Ying Huang (Cleveland Clinic, OH) and colleagues report that apoA1, the primary protein that makes up approximately 75% of HDL particles, is oxidized by myeloperoxidase (MPO) at Trp72, and such oxidation impairs the cardioprotective functions of HDL.

"In the artery wall, within a plaque, the HDL literally gets blown apart," senior investigator Dr Stanley Hazen (Cleveland Clinic, OH) told heartwire . "It gets so heavily oxidized that it's not even a particle anymore. And over 97% of the modified form of apoA1 is no longer sitting on HDL. Even though we're calling it dysfunctional HDL, it's truly dysfunctional. It's been beaten up and broken up to the point where it's no longer an HDL particle."

First Identified Role of MPO, Now This

In 2004, Hazen, who is also the vice chair of translational research at the Lerner Research Institute, published a study showing that apoA1 is a selective target for MPO-catalyzed oxidation, and when this occurs, the HDL is inactivated or becomes dysfunctional. In essence, MPO oxidation prevented reverse cholesterol transport and the ability of HDL to unload cholesterol from cholesterol-loaded macrophage foam cells.

"Since then, we have started mapping where it gets modified and how it gets modified," said Hazen. "The truth is we found over 50 site-specific modifications. We started doing all kinds of mutagenesis studies to find out which residue is important. This led us to focus on the current site, a tryptophan that is critical for the cholesterol-carrying function of apoA1. It took a long time to identify. Even though this is such an abundant product in atherosclerotic plaque, it's evident in very low levels in circulation. We believe it's actually getting made in the artery wall and leeching back out into the bloodstream, and it's this tiny amount that we're detecting."

In the present study, Hazen and colleagues report that apoA1 is metabolized by MPO at Trp72. In vivo and in vitro studies showed that when MPO oxidizes apoA1 at Trp72, it disables the protein's ability to interact with the ATP-binding cassette transporter A1 (ABCA1), the major pathway for loading cholesterol onto the apoA1 particle and forming an HDL particle. The oxidized Trp72-apoA1 complex is found in very low abundance in circulation but accounted for approximately 20% of the apoA1 in atherosclerotic plaque.

When the oxidized Trp72-apoA1 complex was assessed, the researchers found that it exerted a proinflammatory effect on endothelial cells as evidenced by increases in adhesion proteins and proinflammatory markers. In contrast, healthy HDL (as well as apoA1) has anti-inflammatory effects.

In an analysis of 627 individuals presenting to the cardiology clinic, the researchers found that increased plasma levels of oxidized Trp72-apoA1 were associated with increased cardiovascular risk on top of existing risk factors and blood tests. Hazen suggested the whole process might be the result of a "feed-forward" loop, such that apoA1 might get stuck in the artery wall with atherosclerosis, become modified by MPO, and in turn generate the proinflammatory form, a "dysfunctional HDL." The feed-forward loop then exacerbates the whole atherosclerotic disease process.

An assay for oxidized Trp72-apoA1 is expected to be available from Cleveland Heart Lab by the end of the year. What's exciting about this assay, said Hazen, is that it detects not just a marker, but also a molecule involved in the disease process. If oxidized apoA1 can be measured and ultimately lowered, there is hope that doing so might reduce the risk of cardiovascular disease.

The cardiovascular focus on raising HDL-cholesterol levels to prevent clinical events has been hit with disappointments in recent years, with numerous high-profile studies showing that while it's possible to raise HDL-cholesterol levels with various agents, doing so does not translate into clinical benefit.

One of the hypotheses behind such failures, including extended-release niacin in AIM-HIGH and HPS-2/THRIVE and two cholesterol ester transfer protein (CETP) inhibitors, dalcetrapib and torcetrapib , has been that despite raising HDL-cholesterol levels, the HDL particle is dysfunctional.

Hazen, along with three coauthors, reports being a coinventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics or therapeutics. He is a paid consultant to AstraZeneca, Cleveland Heart Lab, Esperion, Lilly, Liposcience, Merck, Pfizer, Procter & Gamble, and Takeda. He reports research funding from the Cleveland Heart Lab, Liposcience, Procter & Gamble, and Takeda. Finally, Hazen reports the right to receive royalty payments for inventions/discoveries related to cardiovascular diagnostics or therapeutics from the Cleveland Heart Lab, Esperion, Frantz Biomarkers, and Liposcience . Other disclosures for the coauthors are listed in the online version of the paper.

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