The Biological Basis for Atherosclerosis

For this article, Jennifer Fisher Wilson interviewed Ronald M. Evans, Howard Hughes Medical Institute investigator and director of the Gene Expression Laboratory at the Salk Institute for Biological Studies in La Jolla, Calif., and Peter Tontonoz, now assistant HHMI investigator and assistant professor in the pathology and laboratory medicine department at University of California, Los Angeles. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. L. Nagy, P. Tontonoz, J.G.A. Alvarez, H. Chen, and R.M. Evans, "Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR- g," Cell, 93:229-40, April 17, 1998. (Cited in more than 170 papers since publication) P. Tontonoz, L. Nagy, J.G.A. Alvarez, V.A. Thomazy, and R.M. Evans, " PPAR- g promotes monocyte/ macrophage differentiation and uptake of oxidized LDL," Cell, 93:241-52, April 17, 1998. (Cited in more than 185 papers since publication) The leading cause of death in the United States and the cause of more than half of all mortality in the world's developed countries, atherosclerosis has long been a disease that puzzled scientists and physicians alike. Atherosclerotic coronary heart disease is the underlying cause for most heart attacks, and one of the most common causes for congestive heart failure, cardiac arrhythmias, and sudden death due to heart attack. The manifestation of the disease was no puzzle. As cholesterol plaque, or lesions, build up in the arteries over time, the risk for disease increases. Predisposing symptoms of the disease include high blood pressure and elevated cholesterol (especially elevated LDL-cholesterol), and smoking, hypertension, diabetes, high cholesterol, and family history of heart disease are known to increase the risk of disease. But despite the prevalence of atherosclerosis and the tremendous interest in the disease, little was known about its biological basis before the 1990s. Then, in 1998, these tandem papers changed the picture of atherosclerosis research. Both papers came from the same research group at The Salk Institute for Biological Studies in La Jolla, Calif. The group submitted the two papers as a package to highlight two different but interrelated components of atherosclerosis. The group provided evidence for how foam cells--the lipid-accumulating precursors of atherosclerotic lesions--are regulated, and information about the body's uptake of oxidized low-density lipoprotein (oxLDL)--a lipid long known as a risk factor in heart disease, but scientists did not previously know how. The research focused on the unexpected role of the nuclear steroid receptor peroxisome proliferator activated receptor g, or PPAR- g, in atherosclerosis. "To cure atherosclerosis, we must understand its molecular biology. Knowing the molecular components will provide us a potential way to promote or antagonize the disease pathway with pharmacological or lifestyle interventions. It also leads the way for drug development and pharmacologic intervention," explains Ronald M. Evans, Howard Hughes Medical Institute investigator and director of the Gene Expression Laboratory at the Salk Institute. "The two papers are really one big story. They provide a mechanism to explain classic cell biology and physiology observations on a molecular level," adds Peter Tontonoz, now assistant HHMI investigator and assistant professor in the pathology and laboratory medicine department at University of California, Los Angeles. Laszlo Nagy, the other principle scientist involved in the research, is now based at the Hungarian Academy of Sciences in Debrecen, Hungary. An earlier, key paper from Evans' lab served as a precursor to these papers. 1 That paper clarified the receptor lipid metabolism and established the link between PPAR- g ligands and fat cells. Evans' lab first undertook research into the connection between PPAR- g and heart disease in 1990. Its role in adipogenesis was discovered in 1994, but at that time there was no hint of a link to heart disease. With those findings, "for the first time, it came together," Evans says. "Those results led us down the road to find the link between PPAR- g and lipid accumulation in atherosclerotic plaque." These subsequent papers provided a novel mechanism to explain how oxidized lipids could directly regulate gene expression and lipid metabolism in macrophages and potentially influence the development of the lesion. "The research demonstrated that PPAR- g is actually expressed in macrophage foam cells within coronary lesions and that oxidized lipids from oxLDL bind directly to PPAR- g, thereby turning on specific macrophage genes," Tontonoz says. The research identified scavenger receptor CD36 as one important gene that is turned on in the pathway. "CD36 is itself responsible for binding and internalizing oxLDL," he notes. Together, the three papers represented the beginning steps toward understanding the relationship between PPAR- g and lipid metabolism in the arteries. Since these publications, the group's research has advanced to two specific, related areas. Using knockout genes, the investigators have studied target genes for PPAR- g that might explain the biology and the pathology of foam cell formation. 2 And they have performed searches to uncover PPAR- g target genes. They also have studied the potential for outside intervention in the lipid cycle. One of the questions that arose in the course of their research was that there was no obvious way to break the cycle of lipid accumulation. This was of particular importance because drug therapies for diabetes Type II--typically a weight-related disease, and the single largest risk factor for heart disease--actually stimulate the lipid cycle by promoting the accumulation of oxLDL. In theory, then, these drugs could increase lipid content in the heart, potentially making cholesterol more dangerous. They wondered, was that the case? In recent studies, however, Evans' group found just the opposite of what had been feared. Instead, they found that diabetes Type II drug therapies actually improve heart disease because another action of PPAR- g is the removal of cholesterol. In this new model, PPAR- g takes out the worst lipids from oxLDL, and returns them to the bloodstream to be dealt with elsewhere in the body, Evans says. Image: courtesy Ronald M. Evans A "gamma cycle" superimposed on an atherogenic artery from an LDL receptor null mouse against a transgenic ApoA/ApoB background. Findings like these on the fundamental role of PPAR- g in the biology of this disease have made the nuclear receptor a prime target for research and drug discovery. "Our research led to unexpected findings in the role of this receptor in heart disease and other metabolic and lipid disorders," Evans remarks. "In the past decade, PPAR- g has become a red-hot area for research." Indeed, an entire conference is now devoted to PPAR- g. Although Evans, Tontonoz, and Nagy are now each based at different institutions, their work is still closely connected. "These papers are an example of fabulous collaboration between researchers," Evans said. "Even though we are in different locations, we are still working together to finish up this work while laying the foundation for future studies." Jennifer Fisher Wilson is a freelance writer in Philadelphia. References 1. B.M. Forman et al., "15-deoxy-delta-12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR- g," Cell, 83:803-12, 1995. 2. Y. Barak et al., " PPAR- g is required for placental, cardiac and adipose tissue development," Molecular Cell, 4:585-96, 1999.

The Biological Basis for Atherosclerosis

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October 2000

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