HIV Protease Inhibitors Promote Atherosclerotic Lesion Formation Independent of Dyslipidemia by Increasing CD36-Dependent Cholesteryl Ester Accumulation in Macrophages

Authors

James Dressman, University of Kentucky
Jeanie Kincer, University of KentuckyFollow
Sergey V. Matveev, University of KentuckyFollow
Ling Guo, University of KentuckyFollow
Richard N. Greenberg, University of KentuckyFollow
Theresa Guerin, University of Kentucky
David Meade, University of Kentucky
Xiang-An Li, University of KentuckyFollow
Weifei Zhu, University of Kentucky
Annette M. Uittenbogaard, University of KentuckyFollow
Melinda E. Wilson, University of KentuckyFollow
Eric J. Smart, University of KentuckyFollow

Abstract

Protease inhibitors decrease the viral load in HIV patients, however the patients develop hypertriglyceridemia, hypercholesterolemia, and atherosclerosis. It has been assumed that protease inhibitor–dependent increases in atherosclerosis are secondary to the dyslipidemia. Incubation of THP-1 cells or human PBMCs with protease inhibitors caused upregulation of CD36 and the accumulation of cholesteryl esters. The use of CD36-blocking antibodies, a CD36 morpholino, and monocytes isolated from CD36 null mice demonstrated that protease inhibitor–induced increases in cholesteryl esters were dependent on CD36 upregulation. These data led to the hypothesis that protease inhibitors induce foam cell formation and consequently atherosclerosis by upregulating CD36 and cholesteryl ester accumulation independent of dyslipidemia. Studies with LDL receptor null mice demonstrated that low doses of protease inhibitors induce an increase in the level of CD36 and cholesteryl ester in peritoneal macrophages and the development of atherosclerosis without altering plasma lipids. Furthermore, the lack of CD36 protected the animals from protease inhibitor–induced atherosclerosis. Finally, ritonavir increased PPAR-γ and CD36 mRNA levels in a PKC- and PPAR-γ–dependent manner. We conclude that protease inhibitors contribute to the formation of atherosclerosis by promoting the upregulation of CD36 and the subsequent accumulation of sterol in macrophages.

Document Type

Article

Publication Date

2-2003

Notes/Citation Information

Published in The Journal of Clinical Investigation, v. 111, no. 3.

© 2003 The American Society for Clinical Investigation

The copyright holder has granted the permission for posting the article here.

Digital Object Identifier (DOI)

https://doi.org/10.1172/JCI16261

Funding Information

This work was supported by NIH grants HL-64056 and HL-68509 (to E.J. Smart) and from Bristol-Myers Squibb.

Repository Citation

Dressman, James; Kincer, Jeanie; Matveev, Sergey V.; Guo, Ling; Greenberg, Richard N.; Guerin, Theresa; Meade, David; Li, Xiang-An; Zhu, Weifei; Uittenbogaard, Annette M.; Wilson, Melinda E.; and Smart, Eric J., "HIV Protease Inhibitors Promote Atherosclerotic Lesion Formation Independent of Dyslipidemia by Increasing CD36-Dependent Cholesteryl Ester Accumulation in Macrophages" (2003). Physiology Faculty Publications. 176.
https://uknowledge.uky.edu/physiology_facpub/176