Studies have suggested that a form of so-called good cholesterol, or high-density lipoprotein, can become dysfunctional and instead of protecting against heart disease becomes a promoter of it, actively clogging up and hardening arteries.
Now, new research led by the Cleveland Clinic in the US has discovered the molecular process that makes "good" cholesterol start behaving badly.
They found that Apolipoprotein A1 (apoA1), an important structural molecule that helps transfer cholesterol out of artery walls and send it to the liver for excretion, can become oxidized while in the artery wall. Once oxidized, it loses its protective properties and instead contributes to the development of coronary artery disease.
They describe their findings in a paper published online in Nature Medicine.
Senior author Stanley Hazen, section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart and Vascular Institute at the Cleveland Clinic, says:
"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."
Their findings help explain why, despite the fact extensive studies have reported how high-density lipoprotein (HDL) protects the heart, clinical trials of drugs to raise HDL levels have so far failed to show they significantly improve cardiovascular health.
Oxidized form of apoA1 found in artery walls disrupts cholesterol removal
Also, researchers have recently been finding apoA1, normally abundant in HDL, is present in an oxidized form in diseased artery walls.
For the last 5 years, Dr. Hazen, who is also vice chair of Translational Research for the Lerner Research Institute at the Cleveland Clinic, and colleagues have been developing a way to identify dysfunctional apoA1/HDL and find how it becomes oxidized.
The protein becomes oxidized by a compound called myeloperoxidase (MPO).
In their report of this latest study, they describe showing how in test tubes "oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function," thus disabling the ability to ferry cholesterol out of the artery wall.
They then tested blood from 627 patients attending the Clinic and found higher levels of dysfunctional HDL raised their risk for cardiovascular disease.
The researchers suggest their findings highlight some new possible targets for drugs that might prevent formation of dysfunctional HDL and thus block its promotion of atherosclerosis.
Dr. Hazen says:
"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."
Grants from the National Institutes of Health (NIH) helped to finance the study.
Meanwhile in a study published in JAMA Neurology in 2013, another team of US researchers describe how they discovered a link between cholesterol and brain deposits that cause Alzheimer's. They found both higher levels of HDL - or "good" cholesterol - and lower levels of LDL - or "bad" cholesterol - in the bloodstream were associated with fewer amyloid plaque deposits in the brain. Such plaques are a hallmark of Alzheimer's disease.