Why Bad Things Can Happen to the Heart when “Good” Cholesterol Goes Bad

Newswise — It's yet another example of how a good thing can go bad: Researchers have found evidence in laboratory studies that 'good' cholesterol, renowned for its ability to protect against heart disease, can undergo detrimental changes in protein composition that make it 'bad' for the heart.

Scientists long have suspected that there may be dysfunctional forms of so-called 'good' cholesterol, also called high density lipoprotein (HDL) cholesterol, that can loose their heart-protective effect. But the exact chemical composition of HDL, both good forms and bad, has remained largely unknown, researchers say.

In a study presented today at the 234th national meeting of the American Chemical Society, researchers reported what is believed to be the most detailed analysis to date of the protein composition of HDL. They uncovered surprising new information about HDL, including previously unrecognized proteins that appear to play an important role in maintaining heart health. Their findings could one day lead to new, more accurate lab tests for heart disease as well as new, potentially life-saving treatments for the disease, which is the number one killer in the United States and other developed countries.

"Targeting HDL could represent a new horizon in heart disease diagnosis and treatment," says study leader Jay Heinecke, M.D., of the University of Washington School of Medicine in Seattle. "But simply boosting HDL levels may not be enough to prevent heart disease. You might have to target the right proteins in HDL."

HDL, which removes cholesterol from artery walls, is also suspected of having anti-inflammatory and antioxidant properties. Its evil twin, low density lipoprotein cholesterol (LDL) deposits cholesterol in arteries. To further explore HDL's role in the body, Heinecke and colleagues conducted a detailed analysis of the protein composition of HDL and found 48 proteins, including 22 proteins that play a role in cholesterol metabolism and 13 proteins not previously known to exist in HDL.

Of the proteins identified in HDL, some might play a previously unsuspected role in preventing atherosclerotic plaques from rupturing. The rupture of these plaques, followed by formation of an artery-plugging blood clot, causes most heart attacks, the researcher says. Other important protective proteins identified in HDL may protect heart cells from injury during a heart attack, Heinecke says.

But other components found in HDL have potentially destructive effects in the body by promoting cholesterol accumulation and inhibiting some of the heart-protective effects of other proteins, Heinecke says. Thus, boosting HDL cholesterol levels alone might not protect the heart, he says. Indeed, a major pharmaceutical company recently withdrew an experimental HDL-boosting drug when it was found that the drug caused an increase in deaths and heart problems, Heinecke notes.

A better understanding of the protein components of HDL could therefore lead to new, more accurate tests for predicting or evaluating heart disease, says Heinecke, whose study is funded by the National Institutes of Health. He notes that heart attacks can occur in people whose cholesterol levels appear normal and that conventional diagnostic tests for cholesterol levels do not always give a clear picture of the disease. More effective, targeted HDL-based interventions could potentially save lives, especially when used in combination with statin drugs that target low density lipoproteins (LDL), or bad cholesterol, says Heinecke, who notes that more studies are needed.

"There's still a lot we don't know about heart disease," Heinecke says. "HDL is still a big mystery, but we're closing in on it and we're pretty excited." Important interventions for fighting heart disease include exercise, a well-balanced diet, and taking heart medications as prescribed, experts say.

The American Chemical Society — the world's largest scientific society — is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.

— Mark T. Sampson

The paper on this research, TOXI 125, will be presented at 10:45 a.m., Wednesday, Aug. 22, at the Boston Convention & Exhibition Center, Room 258C, during the symposium, "Mass Spectrometry of DNA and Protein Damages."

Jay Heinecke, M.D., is a professor of medicine at the University of Washington School of Medicine in Seattle.

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ALL PAPERS ARE EMBARGOED UNTIL DATE AND TIME OF PRESENTATION, UNLESS OTHERWISE NOTED

The paper on this research, TOXI 125, will be presented at 10:45 AM, Wednesday, 22 August 2007, during the symposium, "Mass Spectrometry of DNA and Protein Damages." TOXI 125When good cholesterol goes bad: Mass spectrometric approaches for the analysis of dysfunctional HDL

Program Selection: Division of Chemical ToxicologyTopic Selection: Mass Spectrometry of DNA and Protein Damages

Abstract

Posttranslational oxidative modifications of lipoproteins are implicated in the pathogenesis of atherosclerotic vascular disease. Electrospray ionization tandem mass spectrometry (ESI-MS/MS) coupled with liquid chromatography is rapidly emerging as a powerful technique for pinpointing sites of amino acid oxidation within apolipoproteins. Oxidants generated by myeloperoxidase lead to the site specific oxidation apolipoprotein A-I " the major protein in HDL, and these posttranslational modifications are associated with major impacts on the biological function. We have recently used 2-dimensional liquid chromatography ESI-MS/MS to test the hypothesis that proteins implicated in inflammation might be enriched in the HDL of subjects with coronary artery disease (CAD). Our observations suggest that HDL carries a unique cargo of proteins in CAD subjects and that certain of these proteins might make previously unsuspected contributions to the anti-inflammatory properties of HDL.

Researcher Provided Non-Technical Summary

Briefly explain in lay language what you have done, why it is significant and what are its implications (particularly to the general public)

High density lipoprotein (HDL) is popularly known at the "good" form of cholesterol because it removes cholesterol from arteries. A low level of HDL is a powerful risk factor for premature heart disease. Recent studies suggest that in some people HDL may not protect the heart anymore. To understand the role of HDL in heart disease, we used shotgun proteomics to measure the proteins in HDL. We found many proteins not known to be present in HDL, including proteins of the immune system. Certain of these proteins, which may plan a role in inflammation, were enriched in the HDL of humans with heart disease. We also showed that HDL proteins were damaged by freee radiclas in subjects with heart disease.

How new is this work and how does it differ from that of others who may be doing similar research?

Our observations suggest that changes in the protein composition of HDL may play a previously unsuspected role in heart disease.