and Immunoprophylaxis)
Table of contents :
|
|
|
)
after organ transplantation
in a donated organ to a transplant
patient : it is rare, but the chances of it happening long after the donor
was treated are not extremely unlikely.
inhibitors. Calcineurin is required for NFAT
nuclear translocation and transcription of IL-2.
Calcineurin is naturally inhibited by calcineurin
binding protein 1 (CABIN1) and carabin,
which also inhibits the Ras signalling pathway through its intrinsic Ras
GTPase-activating protein (GAP) activity. Expression of Carabin is upregulated
on TCR signalling in a manner that is sensitive to inhibitors of calcineurin,
indicating that Carabin constitutes part of a negative regulatory loop
for the intracellular TCR signalling pathway. Knockdown of Carabin by short
interfering RNA led to a significant enhancement of IL-2 production by
antigen-specific T cells in vitro and in vivo. Thus, Carabin
is a negative feedback inhibitor of the calcineurin signalling pathway
that also mediates crosstalk between calcineurin and Rasref..
(Cipol-N®, Neoral®,
Restasis®, Sandimmune®), discovered by J.Borel
in 1978, used clinically since 1980.
production
,
hypopotassiuria,
hypouricuria
=> hyperuricemia,
(cyclosporine-associated
arteriopathy)
presents a serious management problem
(FK506®, Prograf®, Protopic®;
Fugisawa Pharmaceutical Co. Ltd, Osaka, Japan). This agent binds to FK506-binding
protein (FKBP)-12 to form a complex with calcium, calmodulin and calcineurin.
The ultimate result is inhibition of T-cell activation and inhibition of
various other cytokines, such as IL-2, IL-3, IL-4, IL-5, IFN-g,
TNF-a, and GM-CSF. Tacrolimus is 10 times to
100 times more potent than cyclosporine, presumably because of its greater
affinity for calcineurin. The adverse-effect profile of tacrolimus is similar
to cyclosporine, although the renal dysfunction is more pronounced with
tacrolimus. The drug was first used in liver transplantation and may substitute
for cyclosporine entirely or be tried as an alternative in renal patients
whose rejections are poorly controlled by cyclosporine. Tacrolimus is 10
times to 100 times more potent than cyclosporine, presumably because of
its greater affinity for calcineurin,
hypopotassiuria,
hypouricuria,
(cyclosporine-associated
arteriopathy)
presents a serious management problemref(more
common than with CsA)
to Th2-polarized
immune responses due mainly to down-regulation of the Th1 cytokines
: inhibition of STAT4 phosphorylation is seen within 2 hours, while downregulation
of IL-12Rb1
and b2 chains
occurs after 3 days of treatment. They interfere with the protective and
defense mechanisms of activated macrophages, rather than resident macrophages.
induce apoptosis in macrophages and monocytes, preventing the release of
IL-6 and IL-1
by preventing CD178
/ Apo1L / FasL upregulation via glucocorticoid-induced
leucine zipper (GILZ) and activation of glucocorticoid-induced
TNFR family related (GITR),
which can inhibit CD3-mediated but not Fas-mediated apoptosis. In cases
where glucocorticoids are overexpressed, this balance could be shifted
such that a higher level of activated T cells survive and thus a greater
population of thymocytes that recognize self could survive. Indeed, in
autoimmune disease models in animals and in patients with multiple
sclerosis,
there is a higher basal level of glucocorticoids. Hence long-term corticosteroid
therapy would cause relapses.|
|
|
|
|
|
|
| cortisol
/ hydrocortisone
(Flebocortid®) |
|
|
|
|
|
| cortisone |
|
|
|
|
|
| fludrocortisone |
|
|
|
|
|
| prednisone
(Deltacortene® (5 mg), Deltacortene forte®
(25 mg)) |
|
|
|
|
|
| prednisolone |
|
|
|
|
|
| 6a-methylprednisolone
(Depo-Medrol®, Medrol®, Urbason®,
Solu-Medrol®) |
|
|
|
|
|
| deflazacort |
|
|
|||
| triamcinolone |
|
|
|
|
|
| betamethasone
(p.o., i.v. Bentelan®) |
|
|
|
|
|
| dexamethasone
(i.v. Decadron®, Soldesam®) |
|
|
|
|
,
growth retardation, toxic
cataract.
The side effects of the glucocorticoids, particularly impairment of wound
healing and predisposition to infection, make it desirable to taper the
dose as rapidly as possible in the immediate postoperative period
.
This inhibition blocks new purine synthesis by preventing the synthesis
of guanosine nucleotides necessary for DNA and RNA synthesis. MMF affects
lymphocytes because they are dependent on this purine synthesis pathway
and do not have alternate salvage pathway capabilitiesref
[12]. They also inhibit the maturation/differentiation of DCs, their expression
of costimulatory molecules and their production of IL-12,
but enhance their production of IL-10.
: fingolimod / FTY720 / 2.amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol
hydrochloride (source : Novartis)
- a synthetic derivative of the antifungal agent myriocinref
- causes immunosuppression in animal models of transplantation and autoimmunityref.
Initial observations showed that FTY720 causes apoptosisref,
but subsequent studies have reaised doubt that its pro-apoptotic activity
is responsible for immunosuppressionref.
The drug markedly decreases lymphocyte
recirculation
to blood and peripheral tissues, including inflammatory lesions and graft
sites (i.e. decreases the number of circulating lymphocytes and increases
lymphocyte numbers in the LNsref).
FTY720 treatment makes T-cell homing to LNs less dependent on CCR7.
Interestingly, FTY720 also prevents lymphocyte egress from the thymusref
and from the LNs into efferent lymphaticsref.
Recent studies have shown that FTY720 is phosphorylated by sphingosine
kinase to an active metabolite that resembles sphingosine-1-phosphate (S1P)
and binds to 4 of the 5 known S1P receptors, EDG1
/ S1P1,
EDG3
/ S1P3,
EDG6
/ S1P4,
and EDG8 / S1P5ref1,
ref2.
S1P1 and S1P4 are found on lymphocytes and can modulate
lymphocyte responsiveness to chemokines. Recent findings indicate that
FTY720 enhances the efflux of cysteine leukotrienes from T cells, and this
effect was required for its activity in T-cell homingref.
S1P receptors are also expressed by the endothelium. So, some of the effects
of FTY720 could be caused by action on vascular or lymphatic endothelial
cells. Posology : 1.25 mg daily i.v.reduce
capacity to generate Th1
lymphocytes and down-regulate Th1-lymphocyte
effector functionsref
inhibit dendritic
cell maturation
derivative)
: use with tacrolimus alone shows promise as a steroid-sparing regimen,
especially in patients who would benefit from pancreatic islet transplantation,
where steroids have an adverse effect on islet survival.)
that inhibit de novo purine synthesis.
,
autoimmune hemolytic anemia, and severe, progressive rheumatoid
arthritis
unresponsive to other agents
(27%) and occasionally thrombocytopenia
(5%)ref.
It is recognized that persons with low levels of activity of the enzyme
thiopurine methyltransferase are at increased risk of bone marrow toxic
effects, and consequently many physicians perform an analysis of TPMT activity
before the initiation of azathioprine therapyref.
Excessive amounts of azathioprine may also cause jaundice, anemia, and
alopecia. If it is essential to administer allopurinol concurrently, the
azathioprine dose must be reduced, since inhibition of xanthine oxidase
delays degradation. This combination is best avoided.
.
It is an antimetabolite that binds to dihydrofolic acid reductase, thereby
preventing the reduction of folic acid to tetrahydrofolate. It interferes
with DNA synthesis, repair and cellular replication and, thus, actively
proliferating tissues are in general more sensitive to this effect. The
mechanism of methotrexate's immunosuppressive effect was recently found
to be related to its ability to inhibit the first committed step of purine
biosynthesis in stimulated human T lymphocytesref
[10]
inhibits the expression of COX-2
and lipid peroxidation
inhibits PKA (Ki = 3 mM),
PKC (Ki = 8 mM), MLCK (Ki
= 12 mM) and p56Lck and Syk (Ki
= 15 mM) and activates caspase-3..
Regimen
: oral 2-3 mg/kg day; 0.1 mg/kg/day
inhibit Th1
cell activation and promote Th2
cell differentiation..
antagonists).
They are used in ...
inducers :
: it decreases Ab production, inhibits IL-6 and TNF-a
production, inhibits B cell development, inhibits the growth of naive
CD4 T cells after activation and production of IFN-g
by Th1
lymphocytes.
: dietary supplementation, especially those of the n-3 class, has immunosuppressive
effects on both innate and adaptive immunity through various mechanisms.
The immunosuppressive effects of PUFAs begin with membrane incorporation
and modulation of lipid-protein lateral organization. This in turn inhibits
downstream signaling mediated by T cell receptors and suppresses T cell
activation and proliferation. Next, we review evidence for PUFA-mediated
alteration of major histocompatibility complex class I and II surface expression
and antigen presentation. We propose that PUFAs influence the expression
of major histocompatibility complex by altering its conformation, orientation,
lateral organization, and trafficking, with consequences for recognition
by effector T cells. PUFA acyl chains are unique in modifying membrane
lateral organization and protein function. An important concept to emerge
from these studies is that PUFA acyl chains and cholesterol molecules are
sterically incompatible. By applying this concept to the T cell activation
and signaling model, mechanisms emerge by which PUFAs can modulate membrane
lipid-protein lateral organization. Membrane modification of both effectors
and targets is an important, often overlooked, mechanism of immunomodulation
by PUFAsref.
inhibitorsref,
collectively known as statins, because of their broad and extensive clinically
beneficial effects and their extremely low incidence of side effects, statins
might even be seen as the new aspirinref.
The concentrations of statins in tissues during therapy is unknown but
is probably <10 µmol/Lref.
Statins are used clinically to :ref1,
ref2.
Clinical benefits (reduction in cardiovascular events and mortality) directly
attributed to the cholesterol lowering effect of statins have been extensively
demonstrated in patients with atherosclerosis and cardiovascular diseases
with or without coronary artery disease symptomsref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7.
At present, 5 statins are available in the US and most other Western countries:
atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. It
is estimated that about 25 million people worldwide are currently being
treated with a statin. The number of prescriptions for statins issued in
developed countries in 2000 was almost 30-fold greater than the number
written
in 1991. WHO statistics indicate that there are about 200 million people
worldwide with coronary artery disease, stroke, other occlusive vascular
diseases, or diabetes mellitus. Consequently, a proposal has been made
that tens of millions of people at increased risk of heart attacks and
strokes should begin statin treatment before onset of diseaseref.
(Poynter et al. reported a 47%ref
reduction in the risk of colorectal cancer among long-term statin users
(i.e., > 5 years), as compared with short-term users or nonstatin users.
In contrast, a randomized trialref
and meta-analysesref1,
ref2,
ref3
have found either a slight increase in cancer among statin users or no
relation between statins and cancers. Although trials are often limited
to comparatively young, low-risk patients and have short follow-up, this
difference may result from methodologic limitations in the observational
study by Poynter et al.ref
). 3-hydroxy-3-methylglutaryl coenzyme A reductase activity is upregulated
in left-sided human colon cancerrefref1,
ref2,
ref3,
ref4,
ref5ref1,
ref2,
ref3,
ref4,
ref5
and CML
cells show more LDL processing than normal blood cellsref1,
ref2,
and cholesterol levels in leukemia cells often do not exhibit feedback
repression in high-sterol mediaref.
Rapidly proliferating tumor cells presumably require cholesterol for new
membrane synthesis. However, high cellular cholesterol may also improve
leukemia cell survival and impart relative resistance to therapy. Compared
with their parental cell lines, drug-resistant myeloid leukemia cell lines
show higher HMG-CoA reductase levelsref,
and drug-resistant lymphoid leukemia cell lines have increased cholesterol
and phospholipid levelsref,
suggesting that acute cholesterol responses may contribute to drug resistance.
Consistent with a critical role(s) for the mevalonate pathway in tumor
cell growth and survival, and with the rate-limiting role of HMG-CoA reductase
in this synthetic pathway, statins have in vivo or in vitro
activity against human head and neck, pancreatic, and CNS tumors and against
human myeloid leukemia cells in xenograft modelsref1,
ref2,
ref3,
ref4,
ref5.
Acute renal injuries caused by ischemia, oxidant damage, and ureteral obstruction
increase renal cortical cholesterol contentref.
Cholesterol levels are similarly increased in cultured human HK-2 proximal
renal tubule cells subjected to iron-mediated oxidant stressref.
In these kidney cell models, increased cellular cholesterol makes cells
highly resistant to subsequent damage, producing a state known as "acquired
cytoresistance." Reducing cellular cholesterol levels pharmacologically
blocks acquisition of cytoresistance and can generate profound mitochondrial
dysfunction and death in kidney cells, further demonstrating the critical
role of cholesterol in renal cell homeostasisref.
Although a majority of adult patients with AML initially achieve complete
remission with conventional chemotherapy, most eventually relapse and succumb
to drug-resistant disease. Given this prevalence of drug-resistant AMLs,
a number of workers have examined the potential antineoplastic effects
of the cholesterol-lowering agents commonly known as "statins," either
alone or as chemotherapy sensitizers. 2 groups have shown that lovastatinref
and simvastatinref
can sensitize AML cell lines to cytarabine. A phase 1 clinical study
showed that serum lovastatin concentrations of up to 3.9 µM could
be achieved without significant tissue toxicityref.
Similar doses of lovastatin is toxic to AML cell lines and to primary AML
cell samples but not to lymphocytic leukemiasref.
A subset of primary AML cell samples, but not normal myeloid cells, can
be sensitized to cytarabine and/or daunorubicin by mevastatinref.
Plasma membrane localization is essential to the function of many proteins
that impact cellular proliferation and/or survival. Because the membrane
localization of many of these signaling proteins requires mevalonate-derived
farnesyl or geranylgeranyl isoprenoid modifications, the antitumor effects
of statins have been assumed to be primarily due to their blockade of isoprenylation.
For example, Ras proteins are activated by mutation and/or overexpression
in a large fraction of human tumors, including myeloid leukemias, thereby
contributing to reduced apoptosis, increased cell proliferation, and poor
clinical outcomesref1,
ref2.
Isoprenylation of Ras and other similarly modified membrane proteins is
specifically mediated by farnesyl-protein and geranylgeranyl-protein transferases,
and FTIs can, like statins, induce tumor regression in mice carrying mammary
or lymphoid tumors overexpressing H- or N-Rasref1,
ref2,
ref3.
However, statin toxicity in primary AMLs is variable and not consistently
higher in samples with Ras overexpression or with Ras activated by "hotspot"
mutationsref.
Others have argued that non-Ras geranylgeranylated proteins are important
statin effectorsref.
However, dependence on geranylgeranylation as well as farnesylation can
be dissociated from statin sensitivity in AMLsref.
In addition, statin concentrations necessary to inhibit specific protein
isoprenylation are 100- to 500-fold higher than those required to inhibit
cholesterol synthesis in the same cellsref
and are higher than the concentrations that are toxic to AML cellsref.
The squalene synthase inhibitor zaragozic acid A (ZGA), which disrupts
cholesterol but not farnesyl pyrophosphate and geranylgeranyl pyrophosphate
synthesis, produced cell death only in the cell lines (ie, NB4 and HL60)
that mounted cholesterol increments in response to radiotherapeutic or
chemotherapeutic insults and that exhibited sensitivity to mevastatin.
Cotreatment of NB4 cells with ZGA and either cytarabine or radiation resulted
in a marked attenuation of the cholesterol increment that would otherwise
have occurred in these cells after exposure to cytarabine or radiation
alone. At the same time, the addition of ZGA to cytarabine or radiation
induced at least an additive toxicity in NB4 cells. This association of
increased toxicity with the attenuation of cholesterol increments provides
further credence for the concept of adaptive cholesterol responses as a
cytoprotective mechanism in particular AMLs. One of the arguments that
has been raised in the literature against a role for cholesterol modulation
in the antineoplastic effects of statins has been the inability of exogenous
squalene and free cholesterol to reduce lovastatin toxicity in NB4 cellsref.
However, cells do not always efficiently incorporate free sterols, as was
shown for K562 cells exposed to exogenous squalene and lanosterolref.
On the other hand, cells can efficiently obtain cholesterol from the ambient
environment by receptor-mediated import of LDLref.
Treating NB4 cells with ZGA in a serum-depleted (and hence cholesterol-depleted)
medium resulted in > 70% toxicity within 24 hours, while the addition of
LDL cholesterol (> 95% purity) to these cultures reversed the toxicity
of ZGA, further supporting the vital cytoprotective role of cellular cholesterol
in certain AMLs. These findings do not exclude the possibility that reduced
isoprenylation may contribute to statin toxicity in particular AMLs but
do highlight the possible importance of direct cholesterol modulation in
new antileukemia therapies. Nonstatin drugs that reduce protective cellular
cholesterol may be more desirable for eradicating cholesterol-dependent
leukemias for several reasons. Some AMLs are apparently able to further
up-regulate LDLR activity after treatment with statinsref,
which could limit the ability of statins to decrease protective cellular
cholesterol. In addition, statins apparently block the production of
a mevalonate-derived Ras inhibitor that accumulates when the mevalonate
pathway is instead blocked at a downstream step by a diphosphomevalonate
decarboxylase inhibitorref.
Therefore, statin treatments could potentially favor the growth of tumor
cells that are regulated by this inhibitor, whereas inhibition of cholesterol
synthesis distal to diphosphomevalonate decarboxylase activity would not
have this effect. Consistent with this idea, lovastatin can increase
proliferation in a large number of primary leukemia cell samplesref.
Squalene synthase inhibitors that block cholesterol biosynthesis at the
final committed step of the mevalonate pathway are being tested for hypercholesterolemia
indicationsref1,
ref2,
and squalene synthase inhibitors and other direct cholesterol-modulating
agents should be rigorously tested as chemotherapy sensitizers in AMLref.
The levels of mRNAs encoding HMG-CoA and LDLR are both increased by daunorubicin
(DNR) or cytarabine (ARA-C) treatments in almost 75% of cultured AML samples.
However, < 33% of AML samples significantly increased LDL accumulation
during drug treatments, suggesting that de novo synthesis is
the primary mechanism by which most AML cells increase cholesterol levels
during drug exposures. LDL increments are not correlated with cholesterol
increments in ARA-C–treated AML samples. However, LDL and cholesterol increments
correlate in DNR-treated AML samples where they are measured, suggesting
that a subset of AMLs may rely on increased LDL accumulation during treatment
with particular drugsref.
: rosuvastatin reduced arterial pressure in genetic hypertension and improved
systemic and regional hemodynamics in SHR and WHY hypertensive rat models
independently of cholesterol levelsref
despite the fact that LDL cholesterol is not directly associated with the
risk of stroke. Withdrawal of statin treatment abrogates stroke protection
in miceref;
protect cortical neurons from excitotoxicityref1,
ref2,
ref3.
36% reduction in heart attacks and a 27% reduction in strokes : overall,
the risk of death from strokes and heart attacks was reduced by 24%ref
seen in 2 clinical trials was generally thought to result from favorable
consequences of stringent and adequate lowering of cholesterol levelsref1,
ref2,
ref3.
Anyway it is tempting to argue that the clinical benefit observed with
statins in cardiac transplantation is not the result of the lowering of
cholesterol levels, as was suggested, but rather the result of their demonstrated
role as inhibitors of expression of CIITA. Indeed, the disruption of the
CIITA gene in mice has a very strong, favorable effect on the outcome of
cardiac transplantationref,
confirming that inhibiting CIITA, and thus MHC class II expression, is
beneficial in organ transplantation.
by cultured human monocytes and mouse peritoneal macrophages. The inhibitory
effect of lovastatin on FcR–mediated phagocytosis was prevented completely
by addition of L-mevalonate, farnesyl pyrophosphate,
LDL, or cholesterol to the culture medium. The inhibitory effect of zaragozic
acid was reversed by addition of LDL, but not by the addition of geranylgeranyl
pyrophosphate, to the medium. In addition, the effect of lovastatin on
phagocytosis is a function of cell activation because treatment of cells
with TNF-a or LPS prevented inhibition of phagocytosis
by lovastatin. The inhibition of Fc receptor–mediated phagocytosis of lovastatin
is related to its effect on cholesterol biosynthesis rather than its effect
on the formation of isoprenoidsref.,
the transcription factor for ABCA1
and ABCG1;
so statins may downregulate cholesterol efflux from nonloaded human macrophagesref
mRNA (t1/2, 43 versus 35 hours)
but not transcription => increased expression by 3.8-fold, completely preventing
its downregulation by ox-LDL in vitro (although L-mevalonate
alone did not affect ecNOS expression, cotreatment with L-mevalonate
completely reversed eNOS upregulation by simvastatinref)
=> increased endothelial nitric oxide (eNO) bioavailability (severely reduced
after AMI and in CHF; eNO bioavailability is also increased by HDL, which
activates both ERK1/2 and Akt, resulting in enhanced eNOS protein stability
and subsequent accumulation of eNOS proteinref:
simvastatin also activates the protein kinase Akt, producing a very rapid
improvement in endothelial function that is independent of changes in eNOS
mRNA levels. Simvastatin treatment can attenuate endothelial cell apoptosis
and augment angiogenesis in the ischemic rabbit hind limb model systemref)
=>
mRNA, the rate-limiting enzyme in the first step of de novo tetrahydrobiopterin
(BH4) synthesis, thereby increasing BH4 levels in
vascular endothelial cells. In addition to augmenting eNOS expression,
statins potentiate GTPCH gene expression and BH4 synthesis,
thereby increasing NO production and preventing relative shortages of BH4ref.
activity => enhanced LXR
activation => increased ABCA1
and ABCG1
expression => cholesterol effluxref
and ABCG1
expression directly, through antagonism of LXR
and indirectly through enhanced RhoA geranylgeranylation.
Interestingly, the increased event rate occurred during the first week
after the onset of symptoms and was independent of cholesterol levelsref.
Anyway short-term discontinuation of statin therapy in stable cardiac
patients apparently does not lead to a clinically important increased risk
of ACSsref.,
a transcription factor essential for the expression of MHC II genesref1,
ref2.
MHC-II molecules, expressed on the surface of specialized cells, are directly
involved in the control of the immune response and thus determine rejection
after organ transplantation. Whereas a limited number of specialized cell
types express MHC-II constitutively, numerous other cells become MHC-II+
on induction by the inflammatory mediator IFN-g.
This complex regulation is under the control of the transactivator CIITA,
the expression of which is tightly regulated by several alternative promoters,
operating under distinct physiological conditionsref1,
ref2,
ref3.
CIITA promoter IV is specifically responsible for the IFN-g
inducible expression of CIITA, and thus of MHC-IIref.
Statins may regulate IFN-g–induced MHC-II expression
on APCs and in this way reduce T-lymphocyte activation :,
USF-1, and IRF-1,
which are required for the activity of CIITA promoter IVref.
Atorvastatin treatment led to a significant down-regulation of HLA-DR and
the CD38 activation marker on peripheral T cells, whereas simvastatin up-regulated
both of these molecules. In contrast, superantigen-mediated T cell activation
was inhibited by simvastatin and enhanced by atorvastatin. No significant
effect of statin treatment on inflammatory serum markers was detected.
Thus, immunomodulatory effects of statins on human T cells are first demonstrated
in
vivo and are differentially induced by 2 different statins: atorvastatin
led to a MHC II down-regulation and may therefore be investigated for treatment
of chronic transplant rejection; simvastatin inhibited superantigen-mediated
T cell activation, which might explain reduced mortality of simvastatin-treated
patients with staphylococcal bacteremiaref.
,
CCL2
/ MCP-1,
and CCL5 / RANTES.
Coadministration of mevalonate reversed the effect of statin on leukocyte
recruitment. The inhibition of sterol synthesis by squalestatin did not
have any anti-inflammatory effect, indicating that the biosynthesis of
nonsterol compounds arising from mevalonate is crucial for the in vivo
regulation of cytokine and chemokine production by statins. Their inhibition
by statins may account for the reported anti-inflammatory effects of these
drugs and may provide a biochemical basis for the recently reported effects
of statins in the prevention of cardiovascular disease and mortalityref
in the vessel wall. In addition, rosuvastatin inhibited vascular expression
of p22phox and superoxide production, as well as diminishing
plasma 8-isoprostanes concentrationsref
a-toxin significantly inhibited exotoxin-induced leukocyte rolling
from 71±10 to 14±4.7 cells/min (P<0.01) and adherence
from 14±3.5 to 0.4±0.2 cells (P<0.01). In addition, simvastatin
pretreatment significantly inhibited transmigration of leukocytes
from 10.5±1.2 to 4.2±0.9 (P<0.05) cells, and decreases
by 50% endothelial cell surface expression of adhesion molecule P-selectin.
Furthermore, simvastatin treatment resulted in enhanced expression of eNOS
in the intestinal microcirculationref.
with subsequent reduction in IRAK activity and cytokine and B7-1 expression.
These effects were mediated via inhibition of protein geranylgeranylation
and farnesylation. Effects of statins were reversed by mevalonate. Whereas
wortmannin and LY294002 inhibited the statin effect, incubation with a
specific RhoA kinase inhibitor had no effectref.
production in vitro and in vivoref
was identified as 1 of 25 genes whose expression were upregulated in CAD
and downregulated by statinsref
expression by 50%, an effect that was not reversed by the HMG-CoA reductase
product mevalonic acid (400 µmol/L). Transcription factor analysis
revealed an inhibition by atorvastatin of NF-kB
+ STAT-1-dependent
de novo synthesis of IRF-1, governing cytokine-stimulated
CD40 expression in these cells. One consequence of this statin-dependent
downregulation of CD40 expression was a decrease in CD40L-induced endothelial
IL-12 expressionref.
Statins
reduce the expression of CD40 on atheroma-associated cells in vitro,
as well as on atherosclerotic lesions in situ in patients treated
with statinsref.
These results have been confirmed by other investigatorsref1,
ref2.
Since CD40 and its ligand CD154 have been implicated in several crucial
immunologic pathways, these latest results, together with observation of
the reduced MHC-II expression, provide even more evidence that statins
have the potential to modulate the immune systemref.
Elevated CD40L levels in patients with hypercholesterolemia and ACS, and
elevated sCD40L levels have been associated with increased risk of cardiovascular
events. Statins, glitazones, gpIIb/IIIa inhibitors, and clopidogrel have
been demonstrated to effectively reduce CD40L levels both in vitro and
in
vivo. Abciximab has been shown to reduce the occurrence of death or
myocardial infarction during 6 months of follow-up in patients with ACS
who had the highest levels of sCD40Lref.
mRNA and protein expression. Treatment of 21 normocholesterolemic men with
simvastatin (20 mg/d for 2 weeks) decreased CCR2 protein and mRNA expression
in circulating monocytes. Promoter and EMSA showed that simvastatin activated
a peroxisome proliferator response element in THP-1 monocytes. Moreover,
simvastatin-induced CCR2 downregulation was completely reversed by the
synthetic PPAR-g antagonist GW9662. Simvastatin-treated
monocytes showed little chemotaxis movement in response to CCL2
/ MCP-1,
a specific CCR2 ligand. Treatment of C57/BL6 mice with simvastatin (0.2
µg/g body weight IP, daily for 1 week) inhibited transmigration of
CD80+ monocytes to the MCP-1–injected intraperitoneal space.
Moreover, few circulating inflammatory cells from simvastatin-treated Sprague-Dawley
rats (0.2 µg/g body weight IP, daily for 2 weeks) were recruited
to the aortic wall of hypercholesterolemic littermatesref.-/-
mice, independently of cholesterol lowering. In this model, cholesterol-lowering
effects can be presumed minimal, because hypercholesterolemia is primarily
due to increases in chylomicron remnants and VLDL, which cannot be cleared
by hepatic LDLRs or LRP via high-affinity binding to apoE. The absence
of significant cholesterol-lowering by statins in this model has been experimentally
validated before and used to demonstrate cholesterol-independent anti-inflammatory
effects of simvastatinref.
Surprisingly, in a longitudinal experiment spanning a much longer period
(24 weeks), a significant temporary increase in plasma cholesterol was
observed, the reason for which remains unknown. Although the extent of
atherosclerosis increased over time in both groups and the higher plasma
cholesterol level in the treatment group was associated with a consistent
trend toward larger lesions, the frequency of bleeding into plaques of
the brachiocephalic (innominate) artery was markedly reduced by statin
treatment after 6 weeks and showed a 49% reduction when all time points
were analyzed together. This was accompanied by an even greater reduction
of intraplaque calcification. Animal models of plaque rupture have been
severely criticized in the past, and none more than murine modelsref.
It is now well established that several transgenic and knockout models
develop advanced atherosclerotic lesions not only in the aortic origin,
where particular anatomic and hemodynamic conditions may influence its
pathogenesis, but throughout the entire aorta, major aortic branch sites,
and coronary arteriesref1,
ref2,
ref3,
ref4,
ref5.
The occurrence of plaque rupture in mice has long been denied, but again
"the mouse may get the last laugh"ref.
Superficial and deep plaque erosion, intraplaque bleeding, occasional thrombi
originating from the necrotic core of advanced atheroma, and blood-filled
channels consistent with revascularization of a ruptured plaque have all
been described in miceref1,
ref2,
ref3,
ref4.
However, substantial anatomical, physiological, and hemodynamic differences
between human and murine plaques impose a very cautious extrapolation of
the results obtained in murine models to humans. For example, the murine
media consists of just a few cell layers and their lesions have a far greater
propensity to invade the media, often resulting in the formation of aneurysms.
Murine lesions fitting the definition of early fatty streaks, ie, consisting
mainly of foam cells, frequently cause significant stenosis that may lead
to altered flow and shear stress, whereas equivalent lesions in humans
have negligible hemodynamic consequences. Pronounced sex differences in
immune-related functions are also increasingly noted in mice, and differences
between human and murine coagulation system may existref.
Nevertheless, human and murine vulnerable plaques have many common features
and manifestations of plaque instability may be less different than presently
assumed. Murine models would be particularly attractive because of the
relative ease with which genes implicated in atherogenesis, arterial remodeling,
and plaque rupture can be manipulated in mice, and because microarrays
are available that permit the simultaneous assessment of the differential
expression of many murine genes in vivoref.
-/-)
developed by Krieger’s group are characterized by very early and extensive
atherogenesis, even when fed normal chowref.
Their coronary atherosclerosis is comparable to that in 2-year-old apoE
miceref
and shows extensive fibrin deposits indicative of plaque hemorrhage and
coagulation. Most importantly, this is associated with multiple spontaneous
infarctions with characteristic ECG abnormalities, enlarged hearts, defects
of myocardial function (reduced ejection fraction and contractility), tissue
necrosis, and deathref.
This should finally put to rest the notion that mice cannot be models of
plaque rupture, just as the development of the apoE mouse put to rest the
dogma that mice cannot develop "real" atherosclerotic lesions. It also
proves in principle that conditions in mice can be modulated to the point
where their pathogenic events mimic those in humans. This should stimulate
the development of other models. Nevertheless, models closer to the human
may still be needed to corroborate results obtained in mice. It will probably
be only a matter of time until the apoE-/- x SR-BI-/-
model will be used to investigate the mechanisms predisposing to plaque
rupture and to assess the protective effect of statins. In the meantime,
the results of Bea et alref
provide the first in vivo evidence that statins reduce plaque vulnerability
independently of cholesterol lowering. However, several caveats have to
be kept in mind. The first is the relatively high dose of statins in this
and other studies. Although a faster drug metabolism in rodents may attenuate
the physiological significance of this discrepancy, the implications in
terms of the accumulation of statins or active metabolites in cellular
membranes and lipid-rich tissues in general remain a concern. Another caveat
regards the temporary rise in cholesterol. The presumption is that statins
inhibit HMG-CoA reductase and consequently the synthesis of both cholesterol
and isoprenoids in mice, as they do in humans, and that the lack of reduction
of murine plasma cholesterol levels is solely attributable to the prevalence
of lipoprotein particles lacking the ligand for hepatic LDL receptors.
If, however, the rise in cholesterol was not coincidental and the effect
of statins on the mevanolate pathway were different from that in humans,
the relevance of the model and the present findings would be questionable.
In
vivo evidence for genuine pleiotropic effects of statins is sparse.
The present article adds reduced calcification, but offers no additional
insights into the mechanisms actually responsible for plaque instability.
Cholesterol-independent effects of statins on lesion composition that could
contribute to weakening of the cap have previously been established in
monkeysref.
Macrophage-secreted metalloproteinases are thought to be an important cause
of fibrous cap weakeningref,
although the impact of individual enzymes has not been establishedref1,
ref2,
ref3.
This assumption is strengthened by the observation that pravastatin treatment
increases collagen content and decreases lipid content, inflammation, metalloproteinase
expression, and cell death in human carotid plaquesref.
However, other protective effects of statins on macrophages, T cells, and
inflammatory conditions prevailing in plaques and potentially contributing
to plaque ruptureref
cannot be ruled out. Clearly, much more work will be necessary to establish
that specific pleiotropic effects of statins contribute to reduced plaque
vulnerability and rupture in humansref.
Atherogenesis involves the migration of monocytes into the subendothelial
spaceref,
where they adhere to matrices containing oxidized
LDLs (oxLDLs),
mature into macrophages, and secrete growth factors, proteases, and ROSref.ref
:
there is now compelling evidence that statin therapy may attenuate the
effect of inflammation on risk of cardiovascular events. Among 708 postinfarction
patients in the Cholesterol and Recurrent Events (CARE) trial, subjects
with elevated levels of CRP and SAA (>90th percentile) had a higher risk
and benefited more from therapy with pravastatin 40 mg/d than those without
elevated levels of these inflammatory markers. The relative risk of a recurrent
coronary event was reduced by 54% and 25% in the 2 groups, respectively,
compared with placeboref.
At baseline, both subsets had nearly identical plasma lipid and lipoprotein
profiles. Long-term therapy with pravastatin in the CARE trial also reduced
levels of CRP in postinfarction patientsref.
Although baseline median CRP levels for active treatment and placebo were
similar, the median level after 5 years was 21.6% lower in the pravastatin
group than in the placebo group (P=0.007). The change in CRP levels associated
with pravastatin treatment was not correlated with the reduction in LDL-cholesterol
levels. The latter finding has been confirmed in the recent 24-week prospective
Pravastatin Inflammation/CRP Evaluation (PRINCE) trialref.
A 6-week triple crossover trial compared the effect of pravastatin, simvastatin,
and atorvastatin therapy on hs-CRP levels in patients with combined hyperlipidemiaref.
All 3 drugs, at doses reported to have equivalent effects on LDL-cholesterol,
significantly reduced median hs-CRP levels (pravastatin by 20%, simvastatin
by 23%, and atorvastatin by 28%), and these reductions were not correlated
with reductions in LDL-cholesterol. This study is in contrast to the negative
result of a similar comparison using a parallel design and a 3-month exposure
with a smaller number of subjects in each subsetref.
In the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP)
study, aggressive statin therapy (atorvastatin 80 mg) reduced CRP levels
to a greater extent than conventional therapy (simvastatin 40 mg)ref.
Moreover, a significant correlation was found in univariate analysis between
the decrease in CRP and the reduction of intima media thickness (IMT) of
carotid artery segments. A recent study showed that simvastatin lowered
CRP within 14 daysref,
independently of LDL-cholesterol reduction. Rapid reductions in CRP levels
with statins could explain in part the early beneficial effects of these
drugs in acute coronary syndromesref.-60,
-65, and -70 antibody titers, positively related to risk of vascular
disease and cardiovascular endpoints, are significantly higher in dyslipidemic
patients with or without established coronary disease. In dyslipidemic
patients, the major dietary predictors of the variability in anti-HSP-60
titers were vitamin C, vitamin E, and total fat intakes; for anti-HSP-65
titers, vitamin C w