Lipid discovery could offer new treatment for heart disease

Kathleen Blanchard's picture
Keeping arteries soft may be an important way to combat heart disease.
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Researchers at the Perelman School of Medicine, University of Pennsylvania, Wistar Institute, and The Children's Hospital of Philadelphia have made a discovery about what causes hardening of the arteries or atherosclerosis that leads to heart disease. The finding could mean a new way to protect from heart disease.

In their studies, the scientists discovered the protein apolipoprotein E (apoE) keeps arteries soft so they can expand and relax.

Patients who take statins that are cholesterol lowering drugs are often unable to tolerate them because of side effects of muscle and joint pain. The medications also require careful monitoring because they can adversely affect liver function.

“Perhaps there are other routes that you could use, independent of cholesterol and statins, that could help keep atherosclerosis at bay," says co-first author Devashish Kothapalli, PhD in a press release. "We think controlling stiffening is one of those. We showed in the paper that even when cholesterol is remarkably high, if you soften tissues back to a healthy level, atherosclerosis is inhibited."

Some people who take statins, aspirin and other blood thinners continue with worsening heart disease that leads to repeated heart attacks and the need for interventions like stenting, angioplasty and bypass surgeries.

Disease of the arteries not only affects the heart. When arteries become hardened blood flow to the major organs and extremities can become impaired. The result can lead to clots and poor blood flow can lead to stroke, kidney dysfunction and peripheral artery disease (PAD) – a painful condition that makes it difficult to walk. Stiffening of the arteries makes high blood pressure difficult to treat. Uncontrolled hypertension can also lead to stroke, congestive heart failure and serious kidney disease that can result in the need for dialysis.

Shu-Lin Liu, PhD, who also helped lead the study explains, “Targeting arterial stiffening could also provide added benefit for patients already on statins. “Ultimately we would hope that controlling stiffening could be used in conjunction with a statin for the large percentage of people who are already on statins but need extra help."

Researchers already know the apoE protein plays an important role in removing cholesterol from the bloodstream to the liver. There is some suggestion that alterations in the apolipoprotein E gene contributes to heart disease. ApoEs belong to a specific type of lipids that are fatty substances called very low-density lipoproteins (VLDLs).

The proteins are also part of the good or HDL cholesterol that helps prevent heart disease. Researchers haven’t been sure why HDL or high density lipoproteins contribute to better heart health. The new study suggests it may be that HDL that contains apoE promotes softness of the arteries.

The researchers used mice in their studies, comparing apoE gene expression between regular mice and mice that lacked apoE.

Mice that lacked the protein were also found to have significantly higher markers of arterial stiffening that included the proteins collagen, fibronectin, and lysyl oxidase that accompanied severe and thorough sclerosis of the aorta – the largest artery in the body.

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Researchers wanted to see if they could reverse the process, so they fed the mice a high-fat diet and treated them with a lysyl oxidase inhibitor, which softened their arteries.

Even though the mice continued to show high cholesterol levels there was a marked improvement in their atherosclerosis.

Senior study author Richard K. Assoian, PhD, professor of Pharmacology said, "It might be the apoE HDL fraction that you need to keep high and not worry about the total HDL.” Because apoE is only about 6 percent of total HDL, "it could go up sky high or not at all, and you probably wouldn’t detect it in these studies that try to raise total HDL."

The study authors think there are other ways to control heart disease, based on the study findings.

Co-first author Devashish Kothapalli, PhD said in a press release, "We think controlling stiffening is one of those. We showed in the paper that even when cholesterol is remarkably high, if you soften tissues back to a healthy level, atherosclerosis is inhibited."

The drug, BAPN (Beta-amino propiononitrile) used in this study would need refining to help humans with heart disease because there are too many side effects. The goal, according to Shu-Lin Liu, would be to develop something that really targets stiffness of the arteries without interfering with balance of other lipoproteins in the body.

The finding shows a potential new drug approach for thwarting heart disease that promotes elasticity of the arteries

Other ways to keep the arteries flexible include eating a diet that includes fish, nuts, and oatmeal and low-fat dairy products. Vegetables and fruits that contain the nitric oxide producing compound arginine and folic acid also promote healthy arteries. Exercising, stretching daily or just staying active throughout the day also promotes nitric oxide formation in the body that helps relax blood vessels can prevent your arteries from becoming stiff and narrow.

Source:
Penn Medicine
November 1, 2012

Resources:
National Institutes of Health
ApoE gene

Clinicaltrials.gov
“Effect of Folic Acid Treatment in Coronary Artery Disease”

Journal of Nuclear Medicine
“Effect of BAPN on Lipid Deposition in Rat Liver and Aorta. Studies Using 4-14C-Cholesterol”

Image credit:
CDC Public Health Library

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