Drug combo may reduce protease inhibitor-related hardening of th...( sis by ubiquitination and degradation o...)

sis by ubiquitination and degradation of protein kinase C," was carried out by Emily L. Bradshaw, Xian-An Li, Theresa Guerin, William V. Everson, Melinda E. Wilson, Annadora J. Bruce-Keller, Richard N. Greenberg, Ling Guo, Stuart A. Ross and Eric J. Smart. The researchers are from the University of Kentucky and the Veterans Administration Medical Center in Lexington. The American Physiological Society published the study.

Long-term side effects a concern

Protease inhibitors have been effective in prolonging the lives of people with AIDS, so much so that patients now survive long enough to develop side effects that are years in the making. One such side effect is atherosclerosis, the accumulation of cholesterol and foam cells in the arteries, causing the vessels to narrow and harden.

Atherosclerosis is a problem in the general population, but protease inhibitors accelerate the process by increasing production of the protein CD36 within macrophages, which fight infections by consuming unwanted materials. CD36 spurs macrophages to eat cholesterol: The more CD36 the body produces, the more cholesterol the macrophages consume.

The problem occurs when cholesterol-laden macrophages get stuck in artery walls. Over time, they accumulate, block the arteries and can result in heart attacks. Because protease inhibitors prompt the CD36-rich macrophages to accumulate more cholesterol, the cholesterol and foam cells build faster and thus lead the arteries to harden more quickly, Smart explained.

Ritonavir produces greater blockage

The researchers examined macrophages isolated from mice receiving ritonavir, a protease inhibitor, and d4T and didanosine, both NRTIs. "NRTIs completely prevented the upregulation of CD36 and the development of atherosclerosis," the authors wrote. Their results also suggest that the NRTIs prevented the increase in CD36 by decreasing protein kinase C, an enzyme that changes the fun
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Contact: Christine Guilfoy
cguilfoy@the-aps.org
301-634-7253
American Physiological Society
5-Sep-2006

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