Protein variant may boost cardiovascular risk by hindering blood vessel repair

September 17, 2014

DALLAS - September 17, 2014 - Researchers at UT Southwestern Medical Center have found that the most common variant of the circulating protein apolipoprotein E, called apoE3, helps repair the lining of blood vessels. Individuals with another variant, called apoE4, do not get the benefit of this repair, putting them at higher risk for cardiovascular disease.

"We believe that we have identified one mechanism by which apoE3 promotes a healthy cardiovascular system and why a genetic variant, apoE4, is detrimental," said Dr. Philip Shaul, Professor of Pediatrics and Vice Chair for Research in the Department of Pediatrics at UT Southwestern.  

The team of researchers found that apoE3 binds to a receptor, ApoER2, and that together they act on endothelial cells, which are the guardian cells of blood vessels, to produce a molecule called nitric oxide (NO). Nitric oxide blunts inflammation, a process that contributes to a variety of vascular disorders.

Up to 15 percent of individuals possess the gene coding for apoE4, and why these individuals are at increased risk of atherosclerosis and coronary heart disease had previously been enigmatic. Using both cell culture and mouse models, researchers showed that in contrast to apoE3, apoE4 cannot activate endothelial cells to produce NO. The reparative and anti-inflammatory processes, therefore, do not occur. In fact, apoE4 prevents the actions of apoE3, explaining why even individuals with one copy of the apoE4 gene are at increased risk of vascular disease.

Using mutant proteins, the investigators further determined the structural feature of apoE4 that prevents the protein from having the favorable actions of apoE3 and instead causes it to antagonize cell responses to apoE3.

The findings, recently published online in the Proceedings of the National Academy of Sciences, also suggest a potential preventive treatment for cardiovascular disease in the high-risk individuals who have the apoE4 variant.  

"An important mechanism that is lost when people possess apoE4 is the ability to produce NO, which leads to a loss of both the reparative and anti-inflammatory capacities of the endothelium," said Dr. Shaul, who holds the Associates First Capital Corporation Distinguished Chair in Pediatrics. "Now, knowing this information, we believe such individuals may benefit from treatment with an NO donor. There is a form of aspirin, for instance, that is an NO donor," he added.

Whereas there is considerable understanding of the biology of the apoE-ApoER2 tandem in the central nervous system and in Alzheimer's disease, the basis for the cardiovascular impact of the receptor and apoE variants had been perplexing. The new findings on apoE and ApoER2 complement the team's prior work on ApoER2, which revealed an important role for the receptor in the blood-clotting disease known as the antiphospholipid syndrome.
-end-
Other UT Southwestern researchers on the team include Dr. Joachim Herz, Professor of Molecular Genetics, Neurology and Neurotherapeutics, and Neuroscience, and also holds the Thomas O. and Cinda Hicks Family Distinguished Chair in Alzheimer's Disease Research; Dr. Robert Gerard, Associate Professor of Molecular Biology; Dr. Eunjeong Jung, postdoctoral fellow; Ivan S. Yuhanna, senior research associate; Mohamed Ahmed, research assistant; and Dr. Chieko Mineo, Associate Professor of Pediatrics.

The study was supported by the American Heart Association and the National Institutes of Health. Additional support was provided by the Crystal Charity Ball Center for Research in Pediatric Critical Care and the Associates First Capital Corporation Distinguished Chair in Pediatrics, as well as the Lupe Murchison Foundation, the BrightFocus Foundation, and the Ted Nash Long Life Foundation.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. Numbering more than 2,700, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to nearly 91,000 hospitalized patients and oversee more than 2 million outpatient visits a year.

UT Southwestern Medical Center

Related Cardiovascular Disease Articles from Brightsurf:

Changes by income level in cardiovascular disease in US
Researchers examined changes in how common cardiovascular disease was in the highest-income earners compared with the rest of the population in the United States between 1999 and 2016.

Fighting cardiovascular disease with acne drug
Researchers from the European Molecular Biology Laboratory (EMBL) in Heidelberg and Stanford University have found the cause of dilated cardiomyopathy - a leading cause of heart failure - and identified a potential treatment for it: a drug already used to treat acne.

A talk with your GP may prevent cardiovascular disease
Having a general practitioner (GP) who is trained in motivational interviewing may reduce your risk of getting cardiovascular disease.

Dilemma of COVID-19, aging and cardiovascular disease
Whether individuals should continue to take angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the context of coronavirus disease 2019 (COVID-19) is discussed in this article.

Air pollution linked to dementia and cardiovascular disease
People continuously exposed to air pollution are at increased risk of dementia, especially if they also suffer from cardiovascular diseases, according to a study at Karolinska Institutet in Sweden published in the journal JAMA Neurology.

New insights into the effect of aging on cardiovascular disease
Aging adults are more likely to have - and die from - cardiovascular disease than their younger counterparts.

Premature death from cardiovascular disease
National data were used to examine changes from 2000 to 2015 in premature death (ages 25 to 64) from cardiovascular disease in the United States.

Ultrasound: The potential power for cardiovascular disease therapy
In the current issue of Cardiovascular Innovations and Applications volume 4, issue 2, pp.

Despite the ACA, millions of Americans with cardiovascular disease still can't get care
Cardiovascular disease (CVD) is the leading cause of death for Americans, yet millions with CVD or cardiovascular risk factors (CVRF) still can't access the care they need, even years after the implementation of the Affordable Care Act (ACA).

Excess weight and body fat cause cardiovascular disease
In the first Mendelian randomization study to look at this, researchers have found evidence that excess weight and body fat cause a range of heart and blood vessel diseases (rather than just being associated with it).

Read More: Cardiovascular Disease News and Cardiovascular Disease Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.