Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases?
Arthritis Research & Therapy
Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases? David W McCarey1, Naveed Sattar2 and Iain B McInnes1
Corresponding author: Iain B McInnes
0 Department of Vascular Biochemistry, Glasgow Royal Infirmary , Glasgow , UK
1 Centre for Rheumatic Diseases, Glasgow Royal Infirmary , Glasgow , UK
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 for statins in modifying endothelial function, particularly with respect to adhesion molecule expression and apoptosis. Broader effects on leukocyte function have now emerged including altered adhesion molecule expression, cytokine and chemokine release and modulation of development of adaptive immune responses via altered MHC class II upregulation. In vivo data in several inflammatory models, including collagen-induced inflammatory arthritis and experimental autoimmune encephalomyelitis, suggest that such effects might have immune-modulatory potential. Finally, a recent clinical trial has demonstrated immunomodulatory effects for statins in patients with rheumatoid arthritis. Together with their known vasculoprotective effects, this growing body of evidence provides compelling support for longer-term trials of statin therapy in human disease such as rheumatoid arthritis.
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Introduction
Statins were developed and tested clinically on the basis
of their capacity to suppress cholesterol biosynthesis and
thereby modify an important vascular risk factor.
Numerous clinical studies have demonstrated efficacy in
this respect, both in secondary and primary prevention
strategies. A significant recent advance in understanding
vascular risk has identified the utility of C-reactive protein
(CRP) and, by implication, inflammation as an important
pathogenetic factor in atherogenic pathogenesis. In
parallel, there has been increasing recognition that the
vasculoprotective effects of statins might reside not only in
lipid modification but also in direct effects on inflammation
manifested presumably through direct effects on the
vascular lesion, or via secondary modification of the
hepatic acute-phase response and constituent moieties,
particularly CRP. CRP measured in this context is typically
of low concentration measured via high-sensitivity assays.
A logical question arising from such studies concerns the
capacity of statins, or statin-sensitive pathways, to operate
in the context of high-grade inflammation such as that
characteristically seen in autoimmune diseases such as
rheumatoid arthritis (RA).
Pharmacology of the HMG-CoA reductase
inhibitors
The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A
(HMGCoA) reductase catalyses the conversion of HMG-CoA to
mevalonic acid and is a rate-limiting step in the cholesterol
biosynthetic pathway. Statins are selective, competitive
inhibitors of this enzyme and are effective lipid-lowering
drugs in humans. They decrease hepatic cholesterol
synthesis, promoting the upregulation of low-density
lipoprotein (LDL)-cholesterol receptors and increasing the
removal of LDL-cholesterol from the plasma [1]. Numerous
derivatives generated in this pathway, including
squalenederived moieties, farnesyl pyrophosphate and
geranylgeranyl pyrophosphate (GGP), in turn might interact with
additional cell signalling pathways, some of which might
have immune-modulatory potential. Five statins are
currently available within the UK: pravastatin, simvastatin,
fluvastatin, atorvastatin and rosuvastatin; in addition,
lovastatin is available in other countries. Cerivastatin has
been withdrawn from sale because of concerns over
adverse events [2] (Fig. 1).
Lovastatin is a fungal metabolite, of which pravastatin and
simvastatin are semi-synthetic derivatives, whereas
fluvastatin, atorvastatin and rosuvastatin are entirely
synthetic [1]. Lovastatin and simvastatin are of the lactone
CI = confidence interval; CIITA = class II transactivator; CRP = C-reactive protein; GGP = geranylgeranyl pyrophosphate; HMG-CoA =
3-hydroxy3-methylglutaryl-coenzyme A; HUVEC = human umbilical-vein endothelial cells; ICAM = intercellular cell-adhesion molecule; IFN = interferon; IL =
interleukin; LDL = low-density lipoprotein; LFA = leukocyte function antigen; MCP = monocyte chemotactic protein; NFB = nuclear factor B;
PPAR = peroxisome-proliferator-activated receptor; RA = rheumatoid arthritis; Th = T helper; TNF = tumour necrosis factor; VCAM = vascular
celladhesion molecule.
Molecular structures of some of the HMG-CoA reductase inhibitors. (From [3]; reproduced by permission of The American Society for
Pharmacology and Experimental Therapeutics.)
pro-drug form, whereas ato (...truncated)