Researchers at the Duke University Medical Center have demonstrated that the progression of the artery-clogging disease atherosclerosis is linked to the inability of specialized bone marrow cells to continuously repair damage to the arterial lining.

The researchers also identified characteristic clusters of genes expressed at distinct phases of disease progression.

The Duke cardiologists and geneticists believe that the findings of their latest experiments represent a new paradigm for understanding and potentially treating atherosclerosis. They said their finding represents the first time the progression of any chronic disease has been linked to a deficiency in the body's repair machinery.

Atherosclerosis is marked by the thickening and clogging of blood vessels, which over time can deprive the heart of necessary oxygen and nutrients. While risk factors such as poor diet, smoking, high cholesterol levels and inactivity are important in developing atherosclerosis, the researchers now believe that heredity plays a crucial role in how the body responds to these environmental factors.

" These results provide us with an intriguing new understanding of the disease process involved in atherosclerosis," said Duke cardiologist Pascal Goldschmidt, senior member of the research team and chairman of Duke's Department of Medicine. The results of the Duke studies were published in the the Proceedings of the National Academy of Sciences ( PNAS ). The study was supported by the National Institutes of Health.

" It appears that the disease progresses as the body's intrinsic ability to repair and rejuvenate itself somehow becomes deficient," Goldschmidt continued. " It is exciting for us think that if we as physicians could somehow stimulate or maintain a successful repair process in heart patients, we might be able to prevent the development of atherosclerosis even if we can't completely control other risk factors, such as high lipid levels or hypertension."

The disease process usually begins with an immune system response to an insult or injury to the arterial lining, said Goldschmidt. Once there, these cells recruit lipids and other fatty materials to the damage site, essentially creating a scar. Over time, the affected arterial cells themselves change, creating a narrower and less elastic artery.

The Duke team focused on the role of a specialized bone marrow cells known as vascular progenitor cells ( VPC ). These cells circulate throughout the blood stream, respond to the initial damage to the arterial lining and initiate the repair process.

" In our latest experiments, we have demonstrated the natural molecular history of atherosclerosis based on the expression of distinct gene clusters and how changes in VPCs are associated with the progression of disease," said Duke cardiologist David Seo, senior author of the paper. " This is the first time the progression of a chronic disease has been linked to changes in the body's ability to repair itself."

For their experiments, the researchers used a well-studied strain of mice whose responses to arterial damage closely parallel that of humans. They fed the mice high-fat diets at different ages. Based on the level of disease found in the aortas of mice, they classified the mice as having no disease, early disease, intermediate disease and moderate disease.

The researchers then performed a DNA microarray, or gene chip, analysis of the activity of genes in aorta samples from each of the four groups. Using this novel technique, researchers can quickly screen more than 12,500 known genes, searching for those that are "turned on," or expressing themselves.

" We found distinct gene clusters, or what we call metagenes, that were activated in each group," said Ravi Karra, first author of paper. " We know that there won't be one 'big bang' gene involved in a process such as atherosclerosis. These metagenes are like fingerprints, which are specific and unique."

Specifically, the researchers found characteristic activity in 197 genes associated with the transition from no disease to early disease; 146 genes associated with transition from early to intermediate disease; 110 genes associated with the transition from intermediate to moderate disease; and 650 genes associated with the transition from no disease to moderate disease.

Interestingly, they said, the bulk of the genes expressed in the initiation of disease were found to play a role in lipid and lipoprotein metabolism. These genes are known to influence the metabolism of the arterial wall by controlling the passage of cholesterol. Genes over-expressed in the transition from early to intermediate disease group tended to fall in the area of the immune response and inflammation. For the transition from intermediate to moderate, genes that actually control the remodeling of arterial wall were over-expressed.

With the knowledge of which genes were over-expressed at each stage of disease, the researchers then compared the findings in mice to that of humans and found the results to be strikingly similar.

" The genes we have identified may represent important modifiers of susceptibility and resistance to atherosclerosis," Goldschmidt said. " These findings could have clinical implications in that the identified genes may represent new targets for intervention. Additionally, the distinct patterns of gene expression may help us determine how advanced the disease may be in patients."

In past experiments, the Duke researchers demonstrated that injecting VPCs into mice with damaged arteries could repair that damage. Furthermore, they discovered that older VPCs had a less robust repair capacity than younger VPCs.

Armed with this new chronology of genetic expression, or time-line, of the key events in the natural progression of atherosclerosis, the researchers then examined how this information correlated with the age and capability of VPCs.

" Significantly, we discovered that the point in time in the disease where the expression patterns in the aorta begins to change from young VPC to old VPC treatment coincides with the point at which the inflammatory response becomes most noticeable and lesions on the artery start becoming visible," Goldschmidt explained.

Source: Duke University Medical Center, 2005


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