Statin-induced expression of CD59 on vascular endothelium in hypoxia: a potential mechanism for the anti-inflammatory actions of statins in rheumatoid arthritis

نویسندگان

  • Anne R Kinderlerer
  • Rivka Steinberg
  • Michael Johns
  • Sarah K Harten
  • Elaine A Lidington
  • Dorian O Haskard
  • Patrick H Maxwell
  • Justin C Mason
چکیده

Hypoxia, which leads to dysfunctional cell metabolism, and complement activation both play central roles in the pathogenesis of rheumatoid arthritis (RA). Recent studies have reported that mice deficient for the complement-inhibitory protein CD59 show enhanced susceptibility to antigen-induced arthritis and reported that statins have anti-inflammatory effects in RA. We hypothesized that the anti-inflammatory effect of statins in RA relates in part to their ability to increase CD59 expression in hypoxic conditions and therefore to reduce complement activation. Flow-cytometric analysis showed that CD59 expression on endothelial cells (EC) was unaffected by atorvastatin in normoxia (21% O2), whereas in hypoxic conditions (1% O2) an up to threefold dose-dependent increase in CD59 expression was seen. This effect of hypoxia was confirmed by treatment of EC with chemical mimetics of hypoxia. The upregulation of CD59 protein expression in hypoxia was associated with an increase in steady-state mRNA. L-Mevalonate and geranylgeraniol reversed the response, confirming a role for inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and geranylgeranylation. Likewise, inhibition by NG-monomethyl-L-arginine and NG-nitro-L-arginine methyl ester confirmed that CD59 upregulation in hypoxia was nitric oxide dependent. The expression of another complement-inhibitory protein, decay-accelerating factor (DAF), is known to be increased by atorvastatin in normoxia; this response was also significantly enhanced under hypoxic conditions. The upregulation of CD59 and DAF by atorvastatin in hypoxia prevented the deposition of C3, C9 and cell lysis that follows exposure of reoxygenated EC to serum. This cytoprotective effect was abrogated by inhibitory anti-CD59 and anti-DAF mAbs. The modulation of EC CD59 and DAF by statins under hypoxic conditions therefore inhibits both early and late complement activation and may contribute to the anti-inflammatory effects of statins in RA.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

A Flowcytometry Study of CD55 and CD59 Expression on Erythrocytes in Rheumatoid Arthritis Patients

Background: Inappropriate activation or blockage of the inhibition of complement system could cause tissue damages in autoimmune diseases particularly rheumatoid arthritis (RA). Defect in complement component regulation may cause damages to tissues, on the other hand, or the damaged tissue might affect the unnecessary activation of complement components.   Objective: To investigate the expressi...

متن کامل

Study on anti inflammatory effect of scorpion (Mesobuthus eupeus) venom in adjuvant-induced arthritis in rats

Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation of the joints as well as other organs in the body. Adjuvant-induced arthritis models in inbred rats serve as relevant models for RA, having many clinical similarities to this disease. Using honey bee venom as a treatment for Rheumatoid arthritis is an ancient therapy in various parts of the world. However scorpion ve...

متن کامل

Expression of IGF-1, IL-27 and IL-35 Receptors in Adjuvant Induced Rheumatoid Arthritis Model

Background: IGF-1 and certain other cytokines have been shown to exert inflammatory/anti-inflammatory roles in chronic joint diseases. Objective: To assess the effect of IGF-1, IL-27 and IL-35, their interaction and their receptor expression in a rheumatoid arthritis model. Methods: Freund’s adjuvant-induced chronic joint inflammation was operated on 160 male rats. Animals were divided into his...

متن کامل

Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases?

Pleiotropic effects are now described for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines role...

متن کامل

Pharmacology of the HMG-CoA reductase inhibitors

Pleiotropic effects are now described for the 3-hydroxy-3methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines roles...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Arthritis Research & Therapy

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2006