One-cell origin for atherosclerosis?

One-cell origin for atherosclerosis?

Atherosclerotic plaque cells contain genes that cause uncontrolled growth, and these genetic elements, when transferred into other cells, cause them to become cancer-like, New York University researchers have found.

Despite the high prevalence of atherosclerosis, the cause of the condition is one of the great myteries of cardiology. Two major theories have been developed by different researchers at the University of Washington in Seattle. One is the response-to-injury hypothesis, which holds that atherosclerotic plaques appear where the blood vessel has been injured (SN: 3/16/85, p. 170). The other is the monoclonal hypothesis, in which plaques are essentially benign tumors that arise from single smooth-muscle cells.

The NYU report, which appears in the October PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (Vol. 83, No. 20), supplies a mechanism for the monoclomal hypothesis. Arthur Penn, Bruce Mindich and their colleagues looked at the proliferating smooth-muscle cells of atherosclerosis by applying techniques developed for the study of genes that are believed to make single cells grow into cancer.

They started by isolating DNA from human atherosclerotic tissue and normal tissue, and transferring both sets into mouse cell lines. The cells exposed to atherosclerotic DNA lost their normal growth control in the same way they would if exposed to cancer genes, though testing for three known cancer genes indicated they were not present. The normal DNA had no effect on the growth of the mouse cells.

The researchers then injected the atherosclerosis-trnasformed cells into mice. The mice developed tumors at the site of injection, indicating that the transformed cells were viable.

"we've demonstrated that human atherosclerotic plaque DNA contains a genetic element capable of transforming cells in culture, and these cells can give rise to tumors," says Penn. "The results indicate that one or more as-yet-unidentified transforming genes play a role in plaque cells comparable to the role oncogenes play in cancer cells.

"To my knowledge, this represents the first direct experimental support for the monoclonal hypothesis," he says.

Thomas Pearson of Johns Hopkins Medical Institutions in Baltimore, who confirmed some of the early monoclonal work, says of the NYU study, "I think it's intriguing evidence and the best evidence yet that at least some atherosclerosis is marked by error in the genetic material, and that would suggest it may be a neoplastic [cancer-like] event." A monoclonal origin for atherosclerosis doesn't necessarily rule out the response-to-injury hypothesis, he says.

If the monoclonal hypothesis is borne out, the next step is to discover what activates or mutates the responsible gene. Among the possible initiating events, Penn suggests, are viruses or chemical carcinogens. As for the role of of high serum cholesterol in plaque development, Penn says that while it is unquestionably a factor, its role in these particular events is unknown.