Lovastatin-Induced Apoptosis in Macrophages Through The Rac1/Cdc42/JNK Pathway

Document Type

Article

Publication Date

7-1-2006

Publication Title

The Journal of Immunology

Abstract

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. The statin family of drugs has been used successfully in the treatment of hypercholesterolemia for more than a decade. To date, they are still the most powerful drugs for lowering cholesterol levels in blood (1, 2, 3). In addition to their potential role in lowering serum cholesterol levels, clinical trials and in vitro studies have shown that statins have pleiotropic effects on a wide range of cell functions and exhibit overall clinical benefits on cardiovascular diseases. Statin therapy significantly reduces ischemic stroke for patients with established coronary artery diseases (4, 5, 6, 7, 8), and is associated with improved patency of autogenous infrainguinal bypass grafts (9). Atherosclerosis as a chronic inflammatory disease leads to a variety of cardiovascular disorders, such as myocardial infarction, stroke, peripheral vascular disease, and aortic aneurysm in aged people. Clinically, statins slow plaque progression and promote regression of atherosclerotic lesions (10, 11, 12, 13, 14, 15). These beneficial effects of statin therapy are believed to be due, at least in part, to the anti-inflammatory and immunomodulatory properties of statins. Treatment with statins in patients with acute coronary syndromes significantly reduces the levels of inflammatory markers, such as C-reactive protein and serum amyloid A (16, 17, 18, 19, 20). Statins have been found to decrease the activation and recruitment of immune cells, an immune response that contributes to the progression of atherosclerotic development (21, 22). However, the direct impact of statins on immune cells, particularly on macrophages, remains largely unexplored. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of the mevalonate pathway. The mevalonate pathway produces isoprenoids that are critical for diverse cellular functions, ranging from cholesterol synthesis to growth control. Farnesylpyrophosphate (FPP)2 and geranylgeranylpyrophosphate (GGPP), the isoprenoid intermediates of the mevalonate pathway, are also important for the posttranslational modification of a variety of proteins, including Ras and small GTPases, such as RhoA, Rac, and Cdc42. Prenylation of these proteins with the isoprenoids is required for their translocation to the membrane and for cellular functions (23). Rho, Rac, and Cdc42 are among the best characterized small GTPases. Although they display similar biological activities in most cases, each of the GTPases can also mediate distinct cellular functions through interaction with its own downstream effector proteins in different cell types. For example, the serum response element of the c-fos promoter is activated by Rho A, but not Rac1 and Cdc42 (24). Rac1 regulates the activation of NADPH oxidase for the purposes of innate immunity in phagocytes. However, Cdc42 acts as an antagonist in the formation of reactive oxygen species in these cells (25, 26). Evidence for extensive cross talks and cooperation between GTPases and other signal transduction pathways is well documented. Rac1 and Cdc42 can synergize with Raf to activate ERK (27, 28, 29). Furthermore, Rac1 cross talks with PI3K in controlling cell migration and polarity (30). Interestingly, these small GTPases are found to mediate apoptosis in a wide range of cell types. Overexpression of the active form of Cdc42 in Jurkat T lymphocytes induces an increase of ceramide levels, resulting in cell death (31, 32). Both Rac1 and Cdc42 mediate apoptosis induced by diverse stimuli (33). It seems that the contribution of Rac1 and Cdc42 to apoptosis is thought to mainly regulate the activation of the JNK pathways (34, 35, 36). In this study, we investigated the direct impact of lovastatin on macrophages. Our data have shown that lovastatin induces apoptosis in macrophages through enhancing the expression of Rac1 and Cdc42, resulting in the activation of the JNK pathway.

DOI

10.4049/jimmunol.177.1.651

Volume

177

Issue

1

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