Nucleoside reverse transcriptase inhibitors prevent HIV protease inhibitor-induced atherosclerosis by ubiquitination and degradation of protein kinase C.
HIV protease inhibitors are important pharmacological agents used in the treatment of HIV-infected patients. One of the major disadvantages of HIV protease inhibitors is that they increase several cardiovascular risk factors, including the expression of CD36 in macrophages. The expression of CD36 in macrophages promotes the accumulation of cholesterol, the development of foam cells, and ultimately atherosclerosis. Recent studies have suggested that alpha-tocopherol can prevent HIV protease inhibitor-induced increases in macrophage CD36 levels. Because of the potential clinical utility of using alpha-tocopherol to limit some of the side effects of HIV protease inhibitors, we tested the ability of alpha-tocopherol to prevent ritonavir, a common HIV protease inhibitor, from inducing atherosclerosis in the LDL receptor (LDLR) null mouse model. Surprisingly, alpha-tocopherol did not prevent ritonavir-induced atherosclerosis. However, cotreatment with the nucleoside reverse transcriptase inhibitors (NRTIs), didanosine or D4T, did prevent ritonavir-induced atherosclerosis. Using macrophages isolated from LDLR null mice, we demonstrated that the NRTIs prevented the upregulation of CD36 and cholesterol accumulation in macrophages. Treatment of LDLR null mice with NRTIs promoted the ubiquitination and downregulation of protein kinase Calpha (PKC). Previous studies demonstrated that HIV protease inhibitor activation of PKC was necessary for the upregulation of CD36. Importantly, the in vivo inhibition of PKC with chelerythrine prevented ritonavir-induced upregulation of CD36, accumulation of cholesterol, and the formation of atherosclerotic lesions. These novel mechanistic studies suggest that NRTIs may provide protection from one of the negative side effects associated with HIV protease inhibitors, namely the increase in CD36 levels and subsequent cholesterol accumulation and atherogenesis.
Bradshaw
Emily L
EL
Department of Physiology, University of Kentucky, Lexington 40536-0230, USA.
Li
Xiang-An
XA
Guerin
Theresa
T
Everson
William V
WV
Wilson
Melinda E
ME
Bruce-Keller
Annadora J
AJ
Greenberg
Richard N
RN
Guo
Ling
L
Ross
Stuart A
SA
Smart
Eric J
EJ
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism; D050197:Atherosclerosis / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D018955:CD36 Antigens / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D016049:Didanosine / Q000378:metabolism; D004789:Enzyme Activation; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D019438:Ritonavir / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D018119:Stavudine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000378:metabolism
D000975:Antioxidants; D018955:CD36 Antigens; D017320:HIV Protease Inhibitors; D011973:Receptors, LDL; D018894:Reverse Transcriptase Inhibitors; D025801:Ubiquitin; D002784:Cholesterol; D018119:Stavudine; D051571:Protein Kinase C-alpha; D024502:alpha-Tocopherol; D016049:Didanosine; D019438:Ritonavir