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New Drug Protects Against the Hardening of Arteries

PPARs in atherosclerosis: the clot thickens

Study highlights the use of a drug that targets multiple PPARs, particularly PPARalpha and PPARgamma, can be effective in limiting the accumulation of lipid in macrophages and subsequently reversing atherosclerosis

Atherosclerosis, a leading cause of morbidity and mortality in Western nations, is caused by the accumulation of cholesterol-rich lipoproteins that adhere to vessel walls and develop into macrophages. These macrophages, laden with lipid, cause inflammation in the vessel and, over time, formation of a lesion. A family of proteins known as PPARs (PPARalpha, PPARbeta, and PPARgamma) are expressed by cells of the artery wall and drugs that activate PPARalpha and PPARgamma (known as PPAR agonists) are used to treat high lipid levels (such as cholesterol and triglycerides), and type 2 diabetes, respectively. The presence of PPARs in the vessel wall has prompted researchers to investigate the effects of PPAR agonists on atherosclerosis in mice. While studies have shown that PPARgamma agonists are beneficial in the treatment of atherosclerosis in mice, the role of other members of this protein family have remained unclear.

In the December 1 issue of the Journal of Clinical Investigation, Andrew Li and colleagues from the University of California, San Diego compare the effects of PPARalpha, PPARbeta, and PPARgamma agonists on the development of atherosclerosis in a mouse model of this disease. They observed profound protective effects of the PPARalpha agonist GW7647, comparable to the PPARgamma agonist rosiglitazone that is currently used to treat type 2 diabetes. GW7647 also reduced weight gain, and insulin and lipoprotein levels. In contrast, lesion development was not inhibited by a PPARbeta agonist.

In an accompanying commentary, Peter Tontonoz and Antonio Castrillo from the University of California, Los Angeles discuss the mechanism described by Li and colleagues by which lipid accumulation is reduced by these agonists, thereby giving us a greater understanding of the roles of PPAR family members in atherosclerosis. Most importantly, the study highlights that the use of a drug (or drugs) that target multiple PPARs, particularly PPARalpha and PPARgamma, may be effective in limiting the accumulation of lipid in macrophages and subsequently reversing atherosclerosis.

Journal of Clinical Investigation Dec 1, 2004TITLE: Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma.

Commentary at: https://www.the-jci.org/press/23705.pdf