Ritonavir stimulates foam cell formation by activating PKC

Abstract

Alpha-subtype protein kinase C (PKCα) is closely related to cardiovascular disease. Ritonavir (RTV), which is a human immunodeficiency virus (HIV) protease inhibitor, can induce atherosclerosis in a PKC-dependent manner. However, it remains unclear how RTV acts on PKCα to induce pathological phenotypes. In this study, we obtained mouse peritoneal macrophages from adult female Kunmin mice. The results of Oil Red O staining and immunofluorescence using confocal laser scanning microscope demonstrated that RTV could induce foam cell formation and plasma membrane translocation of PKCα like phorbol-12-myristate-13-acetate (PMA, a PKC activator). Computational modeling also exhibited similar docking of RTV and PMA to PKCα and similar patterns of hydrophobic interaction and hydrogen bond formation. Further in vitro kinase activity studies revealed that RTV could elevate PKC activity. These data provided insight into the PKC-dependent induction of atherosclerosis and useful information for more in-depth toxicity research of HIV protease inhibitor (PI). In addition, western blot analysis proved RTV also up-regulate PKCα expression, which may be related to its influence on estrogen responsiveness in target cells and needs further prove.