Lovastatin-induced apoptosis in macrophages through the Rac1/Cdc42/JNK pathway.
Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, have been used successfully in the treatment of hypercholesterolemia for more than a decade. Statins also exhibit overall clinical benefits on cardiovascular diseases independent of their effects on lowering serum cholesterol levels. These beneficial effects of statin therapy are believed to be due, at least in part, to the anti-inflammatory and immunomodulatory roles of statins. Statin treatment reduces the levels of inflammatory markers, decreases the activation and recruitment of immune cells, and delays the progression of atherosclerosis, a chronic inflammatory disease. However, little is known about the direct impact of statins on immune cells, particularly on macrophages. We report that lovastatin, a member of the statin family, effectively induces apoptosis in macrophages. Further investigation of the molecular mechanism has revealed that Rac1 and Cdc42, the small GTPase family members, may play an important role in lovastatin-induced macrophage apoptosis. Moreover, the activation of the JNK pathway may contribute to this event. Our findings provide a better understanding of the molecular basis underlying the anti-inflammatory clinical benefits of statin therapy in cardiovascular diseases.
Liang
Shu-Ling
SL
Clinical Chemistry Program, Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
Liu
Hongli
H
Zhou
Aimin
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008148:Lovastatin / Q000494:pharmacology / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D012717:Sesquiterpenes; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects; D020764:cdc42 GTP-Binding Protein / Q000096:biosynthesis / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000502:physiology*
D006131:Growth Inhibitors; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D008148:Lovastatin; D048031:JNK Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate