Salk researchers find genetic feedback loop implicated in the early events of atherosclerotic plaque formation

April 17, 1998

Salk researchers find genetic feedback loop implicated in the early events of atherosclerotic plaque formation

April 17, 1998

La Jolla, CA – Salk Institute scientists today announced two research findings related to the development of atherosclerosis. The findings involve the discovery of a genetic feedback loop that contributes to the formation of atherosclerotic plaques in heart arteries and the role of a previously described fat storage gene (PPARgamma) in this process.

The work, published in two papers in the April 17 issue of the journal Cell, was directed by Salk Professor Ronald Evans;, PhD The lead authors of the studies were Peter Tontonoz, MD, PhD and Laszlo Nagy, MD, PhD

Researchers believe the form of cholesterol responsible for promoting the plaque formation is oxidized low-density lipoprotein (oxLDL). The Salk studies show that uptake of oxLDL by macrophage cells activates a gene called PPARgamma (previously identified as a receptor involved in fat tissue development and fat storage). This new understanding about the function of PPARgamma makes it the second gene implicated in causing atherosclerosis.

The current studies demonstrate that PPARgamma boosts the production of CD36, a surface receptor that imports oxLDL, thus setting up a positive feedback loop for cholesterol traffic into the cell. Eventually, the macrophage becomes a “foam cell,” the first cell type observed during the formation of atherosclerotic plaques.

The Evans group has previously shown that PPARgamma is also stimulated by thiazolidinediones, which raises the question of whether Type II diabetics taking these widely prescribed drugs might be at increased risk for atherosclerosis. This is an important question, since many diabetics are overweight and already at risk for heart disease. According to the American Diabetes Association, Type 2 diabetes affects approximately 15 million Americans, but the researchers urge caution in interpreting the results announced today.

“Fat cells and macrophages in the liver also produce CD36, which is beneficial in taking up oxLDL and removing it from circulation,” said Nagy. “So, an increase in PPARgamma may actually do more good than harm. What we need to do is figure out how to modulate the PPARgamma/CD36 feedback loop locally, specifically in the arteries.”

The paper “PPARgamma Promotes Monocyte/Macrophage Differentiation and Uptake of Oxidized LDL” is authored by Tontonoz, Nagy, Jacqueline G.A. Alvarez, Vilmos A. Thomazy, MD, PhD, and Evans. Nagy is on leave from the University Medical School of Debrecen, Hungary, and Thomazy is with the University of Texas at Houston. Tontonoz has a joint affiliation with Salk and the University of California, San Diego. The paper “Oxidized LDL Regulates Macrophage Gene Expression through Ligand Activation of PPARgamma,” is authored by Nagy, Tontonoz, Alvarez, Hongwu Chen, PhD, and Evans.

The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution conducting basic science research dedicated to the improvement of human health and improving the quantity and quality of the world’s food supply.

Its two main fields of concentration are neuroscience and molecular-cellular biology and genetics; The Salk Institute was recently ranked the top research institution worldwide in both of these areas by the Philadelphia-based Institute for Scientific Information.

The Salk Institute was founded in 1960 by polio vaccine pioneer Jonas Salk, MD, with a gift of land from the City of San Diego and the finanancial support of the March of Dimes Birth Defects Foundation. Thomas D. Pollard, MD, is President and Chief Executive Officer.