Comments for:
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.
Authors
James Dressman, Jeanie Kincer, Sergey V. Matveev, Ling Guo, Richard N. Greenberg, Theresa Guerin, David Meade, Xiang-An Li, Weifei Zhu, Annette Uittenbogaard, Melinda E. Wilson, Eric J. Smart
Are protease inhibitors possible atherogenetic mechanisms group specific? Is PPARg involved?
Submitter: Magnus B Jensen | magnus.jensen@iekf.au.dk
Research lab-Q and Dep. of Clinical Immunology, Skejby Sygehus, Aarhus University Hospital, Denmark
Published April 2, 2003
We have read the study by Dressman et al(1) with great interest. However, we have some concerns with regard to the results and the interpretation.
First, the authors state their data suggest that ritonavir causes CD36 upregulation by increasing PPARg -levels. Allegedly, CD36 upregulation promotes atherosclerotic lesion formation by increasing macrophage cholesterol ester levels. As the authors state, this is in accordance with the study conducted by Nagy et al(2), in which the PPARg is suggested as one of “the bad guys” in atherogenesis by increasing expression of CD36. However, more recent work has shown that stimulation of PPARg truly causes CD36 upregulation but paradoxically it does not result in accumulation of macrophage cholesterols (3-5). Furthermore, substantial and reliable evidence of PPARg´s numerous antiatherogenetic effects has now been provided(6-9). It could very well be argued that PPARg is actually one of “the good guys”, and an upregulation of PPARg might be speculated to be antiatherogenetic, at least until firm evidence has proved otherwise.
Second, the authors claim to have provided results suggesting the effects of protease inhibitors(PI) to be group specific as opposed to the nonspecific effects of different PIs. It would seem reasonable to examine the patophysiological mechanisms of more than just one compound (ritonavir) as done in this study, before any such general conclusion is drawn. For example, different PIs have been demonstrated to influence lipogenesis and cell differentiation in adipocytes very differently(10- 12).
Third, the authors argue that screening of CD36 (in PBMCs) might be a better marker for possible atherogenesis than plasma lipids in PI treated patients. We suggest this statement to be interpreted in the context of the following consideration. PIs might increase macrophage cholesterol by inhibiting cholesterol efflux as opposed to an increase of the influx (i.e. increasing the CD36). The increase of the CD36 might merely be a response to increased macrophage cholesterol(13;14) and not an accurate marker of the effects of PIs.
Reference List
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