Published online before print May 12, 2009

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(American Journal of Pathology. 2009;174:2007-2014.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080611

Short Communications

Atherosclerosis in LDLR-Knockout Mice Is Inhibited, but Not Reversed, by the PPAR Ligand Pioglitazone

Hideaki Nakaya^*, Barbara D. Summers^*, Andrew C. Nicholson^*, Antonio M. Gotto, Jr., David P. Hajjar^* and Jihong Han^*

From the Center of Vascular Biology,^* the Department of Pathology, and the Department of Medicine, Weill Medical College of Cornell University, New York, New York; and the College of Life Sciences and the Key Lab of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China

Thiazolidinediones, a class of drugs for the treatment of type-2 diabetes, are synthetic ligands for peroxisome proliferator-activated receptor-. They have been demonstrated to possess cardioprotective effects in humans and anti-atherogenic properties in animal models. However, the question remains whether a peroxisome proliferator-activated receptor- ligand can reverse the development of atherosclerosis. In this study, we tested the effects of pioglitazone on the development of established atherosclerosis in low-density lipoprotein receptor-null mice. We observed that atherosclerosis in low-density lipoprotein receptor-null mice progressed when mice were fed a high-fat diet. Pioglitazone treatment of atherogenic mice prevented this progression of atherosclerosis from its middle stages of disease, but was not able to reverse it. Withdrawal of the high-fat diet from mice with advanced atherosclerosis did not result in a reduction in lesion sizes. Pioglitazone treatment also had no effect on advanced atherosclerosis. Levels of high density lipoprotein cholesterol correlated inversely with lesion development when pioglitazone was given during lesion progression. However, pioglitazone had no effect on circulating high density lipoprotein levels in mice in which treatment was initiated following 14 weeks on the high-fat diet. These findings have implications for the analysis of therapeutic agents in murine models of atherosclerosis and the use of pioglitazone in patients with established atherosclerosis.

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