20080107 Monday January 07, 2008

what exactly are statins anyways?

: Med Hypotheses. 2007;68(6):1296-9. Epub 2006 Nov 13.Click here to read Links
Comment in:
Med Hypotheses. 2007;69(3):697.

Statins may enhance the proteolytic cleavage of proBDNF: implications for the treatment of depression.

Department
of Psychiatry, Taipei Veterans General Hospital, No. 201 Shih-Pai Road,
Sec. 2, 11217 Taipei, Taiwan. sjtsai-AT-vghtpe.gov-DOT-tw

The
family of hydroxymethylglutaryl coenzyme A reductase inhibitors,
collectively known as statins, are used clinically to reduce plasma
cholesterol levels. Recent reports indicate that statin therapy is
associated with a reduced risk of depression, although the mechanism
underlying this antidepressant effect is unknown. Evidence suggests
that increasing central BDNF activity plays an important role in the
treatment of major depression. In the nervous system, the proteolytic
cleavage of pro-BDNF, a BDNF precursor, to BDNF through the tissue-type
plasminogen activator (tPA)-plasmin pathway represents one mechanism
that can regulate the action of BDNF. In vitro studies have
demonstrated that statins can induce tPA and inhibit plasminogen
activator inhibitor-1, the major inhibitor of tPA. It is therefore
possible that statins could act through the tPA-plasminogen pathway to
increase BDNF and achieve an antidepressant effect. It is suggested
that statins could be of therapeutic potential for patients with major
depression: especially those that have an abnormality in the
tPA-plasminogen pathway or comorbidities relating to cardiovascular
disease. Furthermore, BDNF dysfunction has also been implicated in
several other neuropsychiatric diseases, such as Alzheimer's disease,
attention-deficit hyperactivity disorder and Rett syndrome. The
potential use of statins in these diseases may warrant further
exploration.

PMID: 17097821 [PubMed - indexed for MEDLINE]





Clinical Papers



Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I


Martin G, Duez H, Blanquart C, Berezowski V, Poulain P, Fruchart JC, Najib-Fruchart J, Glineur C, Staels B. J Clin Invest 2001 Jun;107(11):1423-1432.




Departement d'Atherosclerose, UR 545 Institut National de la Sante et
de la Recherche Medicale (INSERM), Institut Pasteur de Lille and
Faculte de Pharmacie, Universite de Lille II, Lille, France.



In this paper, Martin and colleagues present evidence that links
the pleiotropic and apoAI/HDL raising effects of statins with that of
the mechanism of action of the fibrates; activation of PPARa.



It is now clear that inhibition of endogenous cholesterol production by
HMGCoA reductase inhibitors (statins) can significantly reduce CHD.
Some of this benefit originates in the activation of sterol regulatory
element-binding protein (SREBP), leading to increased LDL clearance.
Statins also appear to be able to lower plasma triglycerides, probably
by increasing remnant clearance and decreasing VLDL construction, as
well increasing the levels of apoAI and anti-atherogenic HDL. In
addition, statins have direct and beneficial anti-inflammatory,
-thrombotic and -proliferative effects on the vascular endothelium
itself. These direct effects can be negated by the addition of
mevalonate or isoprenoids, such as farnesyl pyrophosphate (Fpp) or
geranygeranyl pyrophosphate (GGpp) – downstream metabolites of HMGCoA
reductase; these positive effects can also be mimicked by the addition
of C3 exoenzyme, an inhibitor of Rho activity. As both Rho (and Ras)
require prenylation for activation of the mitogen-activated protein
kinase pathway(MAPK) and NFkb pathways, it appears that statins can
indirectly suppress the activity of Rho and that this suppression leads
to their directly beneficial effects on the endothelium.



It has now been clearly shown that the beneficial effects of the
fibrates are mediated by their effects on PPARs – a series of
ligand-activated transcription factors that belong to a superfamily of
nuclear receptors; their main site of activity is PPARa, which is also
considered to be the main regulator of extracellular fatty acid
metabolism. By their action on PPARa, they can both improve lipid
profiles (increase HDL, decrease VLDL and triglycerides) and exert
anti-inflammatory actions on the vascular endothelium. Because of the
similarities of actions between the statins and the fibrates, Martin
and colleagues theorised about the existence of a common mechanism of
action. To verify their theories, the authors undertook a series of
experiments, which showed the following:
  • That statins could induce the transcription of apoAI mRNA, in
    a dose-dependent manner, in human hepatoma HepG2 cells; this activity
    could be abolished by co-treatment with mevalonate, as well as
    pre-treatment with actinomycin D, a transcriptional inhibitor.
  • That statins could induce apoA-1 promotor activity (a section of
    DNA that controls apoAI gene expression) in transfection experiments
    involving the apoAI promoter linked to a luciferase reporter.
  • That statins could induce apoAI promoter A-site activity by
    activation of PPARa in transfection experiments using a construct made
    from a minimal apoAI promotor and the PPRE (peroxisomal proliferator
    response element, the DNA target for PPARa) in a cell line that is
    devoid of PPARa; without PPARa transfection, statins did not induce the
    apoAI promoter, but in conjunction with PPARa transfection, the site
    could be activated.
  • That statins activate PPARa in a promotor-independent manner via
    its ligand-binding domain (LBD), using a chimeric/luciferase construct
    in which the LBD of PPARa was fused to Gal4 (a yeast transcription
    factor).
  • That statins activated PPARa independently of PPARa ligands (such
    as fatty acids, prostaglandins or phospholipid derived ligands)
    produced by upregulation of SREBP by showing that specific inhibitors
    (e.g., cerulenin) had no effect on statin-induced PPRE-reporter
    activation.
  • That statins activate PPARa by inhibiting the GGpp/Rho signal
    transduction pathway; co-incubation of GGpp, but not Fpp (both
    metabolites of mevalonate), with statins inhibited PPARa activity.
    Additionally, a GG transferase inhibitor (GGTI) upregulated PPARa
    activity, whereas a farnesyl transferase inhibitor (FTI) had no effect.
  • That an inactive version of the Rho molecule, generated using a
    dominant negative Rho A mutation expression vector, could induce PPARa;
    an effect enhanced by fibrate treatment.
  • That statin treatment decreased PPARa phosphorylation activity (Rho
    proteins activate protein kinase pathways); this suggested a possible
    mechanism of how inactivation of Rho may lead to PPARa activation.
  • That coincubation of a statin (cerivastatin) and a fibrate (fenofibrate), synergistically transactivated PPARa.

 


Multiple Effects of Statins in Nonlipid Disease States

Melody Clay Sheffield, PharmD
Public Service Assistant
Regional Coordinator for Southwest Georgia
University of Georgia
College of Pharmacy
Athens, Georgia
 

U.S. Pharm. 2004;6:38-54.

The
3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors,
or statins, have been a primary force in the management of
hypercholesterolemia for many years and are important in the primary
and secondary prevention of heart disease. However, increasingly it is
being shown that the statins have clinical benefits that appear to be
greater than those one would expect from improvement in the lipid
profile alone.1 Emerging evidence of the influence of
statins in diseases such as heart failure, cancer, multiple sclerosis,
osteoporosis, and others requires pharmacists to revisit the mechanisms
whereby these drugs exert their activity. While the use of statins in
many of these disease states will depend on the results of additional
clinical trials, pharmacists need to be aware of potential future uses.
The word pleiotropic means multiple effects, and this paper will review
the pleiotropic actions of the statins.
 

PATHWAYS OF ACTIVITY
Cholesterol
is required in maintaining cellular membrane structure and is also a
precursor for the synthesis of steroid hormones and bile acid.2 The mevalonate pathway (FIGURE 1)
is the series of biochemical reactions leading to the synthesis of
cholesterol. The statins, by inhibiting HMG-CoA reductase, block the
rate-limiting step in this pathway, resulting in decreased cholesterol
production. Blocking cholesterol synthesis has been believed to be the
statins' primary mechanism of action. However, a number of
cholesterol-independent or pleiotropic effects of statins relate to
their ability to block the synthesis of important intermediate
products.


 



Intermediate
products in the mevalonate pathway include isoprenoids such as
farnesylpyrophosphate and geranylgeranylpyrophosphate.1 The
biologic mechanism for most of the pleiotropic effects of statins is
related to inhibition of isoprenoid metabolism in nonhepatic cells (FIGURE 2).3
The Ras family of proteins is necessary for cellular differentiation
and proliferation, while the Rho family is important for cytoskeleton
formation, superoxide generation, and cell growth progression.4
Blocking these important isoprenoid intermediates affects mitochondrial
respiration, lipid peroxidation, posttranslational modifications of
cellular proteins, modifications of certain tRNA, and production of
glycoproteins. Therefore, blocking of the mevalonate pathway by the
statins may have significant influences on many critical cellular
functions.2


 



ACTIONS OF STATINS
Statin
therapy has been found to rapidly improve vasomotor response, enhance
coronary blood flow, and reduce the levels of adhesion molecules. This
is due in part to the ability of the statins to increase endothelial
nitric oxide production secondary to inhibition of Rho and the
resulting up-regulation of endothelial nitric oxide synthase (eNOS).
Endothelial nitric oxide synthase is the enzyme required for nitric
oxide production. Through another unclear mechanism, statins
up-regulate the phosphatidylinositol 3'-kinase/Akt pathway
(PI3-kinase/Akt pathway). This also activates eNOS (FIGURE 3). The antioxidant effects of this group of drugs may also contribute to their ability to improve endothelial function.5


 



Unstable
atherosclerotic plaques are characterized by a lipid-rich core and
excess inflammatory cells. The release of matrix metalloproteases by
macrophages degrades plaque matrix connective tissue, weakening the
fibrous cap. This makes these plaques susceptible to rupture. Statins
have been shown to increase plaque stability by decreasing levels of
metalloproteases, oxidized-low density lipoprotein, core lipid content,
macrophages, and by increasing the collagen content in plaque matrix.6
Through the inhibition of Rho, lovastatin has been shown to increase
tissue plasminogen activator activity while inhibiting plasminogen
activator inhibitor type-1 activity. Thus, statins exert positive
effects on the fibrinolytic profile in the vascular endothelium.7

Statins
may exert anti-inflammatory effects by several pathways. The
isoprenoids have been shown to activate inflammation via intracellular
second messenger systems. Two other pathways include blocking the
function of the integrin lymphocyte function-associated antigen-1
(LFA-1) and action on the phosphatidylinositol 3'-kinase/Akt signal
transduction pathway. Disruption of these pathways may inhibit
lymphocyte recirculation, T-cell activation, and T-cell migration.8
Other mechanisms yet to be fully elucidated may involve inhibition of
adhesion molecules and inhibition of interleukins 6 and 8. High
sensitivity C-reactive protein, a clinical marker of inflammation, is
lower in hypercholesterolemic patients on statin therapy.5

Statins also affect gene expression (FIGURE 4).
Increased gene expression of bone morphogenetic protein-2 (BMP-2)
through statin use resulted in increased bone formation in animal
studies. This drug group has been demonstrated to inhibit the
expression of class II major histocompatibility complex (MHC II) genes.
T-cellactivation is dependent on interactions involving MHC. These
findings indicate that statins may be effective as immunomodulators.9
In addition, in vitro studies with the HMG-CoA reductase inhibitors
have demonstrated the suppression of natural killer cells, inhibition
of chemotaxis by monocytes, regulation of DNA in cycling cells, and the
inhibition of antibody-dependent cellular cytotoxicity.10


 



Statins modify several processes in the cell cycle.11 They have been shown to synchronize tumor cells by blocking the transition of G1-S
in the cell cycle, thereby exerting antiproliferative effects. This is
thought to be secondary to the inhibition of geranylgeranylated
proteins. The depletion of geranylgeranylated proteins also appears to
mediate statin induced apoptosis. Ras inactivation is considered an
important mechanism in the ability of statins to inhibit cell signaling
pathways associated with the invasive and metastatic properties of
cancer.2
 

DISEASE STATES

Cardiovascular Disease
Serum
cholesterol levels are strongly associated with coronary heart disease,
and it has been assumed that cholesterol reduction by statins is the
mechanism underlying their beneficial effects in cardiovascular
diseases. However, rapid reduction in cholesterol levels would not
result in rapid reductions in atherosclerotic lesion size. The changes
in plaque size associated with lipid lowering occur over an extended
time. The benefits of statins in cardiovascular disease likely come
from reduction in lipids and macrophage accumulation in atherosclerotic
lesions with inhibition of matrix metalloproteinases and tissue factor
production resulting in plaque stability.1

Both
the Reduction of Cholesterol in Ischemia and Function of the
Endothelium (RECIFE) trial and the Myocardial Ischemia Reduction with
Aggressive Cholesterol Lowering (MIRACL) study investigated statin use
after acute coronary syndromes. The RECIFE trial indicated that
cholesterol reduction can rapidly improve endothelium-dependent
vasodilation. This improvement in endothelial reactivity did not
corrrelate with a reduction in the various lipid fractions. In the
MIRACL study the benefit of atorvastatin was not dependent on baseline
cholesterol levels. This suggests that the decision to start intensive
lipid-lowering therapy after acute coronary syndrome should not
necessarily be influenced by lipid levels at the time of the event.12,13

Statins
decrease the incidence of chronic heart failure (CHF) in hyperlipidemic
patients probably by lipid lowering and reducing subsequent ischemic
cardiac events. Because statins improve endothelial function and
suppress inflammatory responses, Node et al hypothesized that statins
may improve cardiac function and neurohormonal imbalance in patients
with symptomatic, nonischemic left ventricular dysfunction. The study
demonstrated that short-term statin therapy did provide beneficial
effects in patients with nonischemic dilated cardiomyopathy. These
beneficial effects may be explained, in part, by the reduction in
systemic inflammation. Another contributing factor may be inhibition of
synthesis of isoprenoids resulting in increased endothelial nitric
oxide production and decreased endothelin-1 expression. Finally,
statins may modulate the remodeling process of heart failure through
inhibitory effects on matrix metalloproteinases (MMPs). MMP-9 plays an
important role in the progression to heart failure. Statins suppress
growth of macrophages expressing MMP-9, MMP-3, and MMP-1. Therefore,
statins may improve cardiac function in patients with CHF through
inhibitory effects on MMPs.14 After simvastatin treatment,
fewer instances of new-onset chronic heart failure were observed in the
Scandinavian Simvastatin Survival Study. This effect seems to be
independent of the lipid-lowering features of simvastatin, indicating
that the anti-inflammatory, antiproliferative, and antioxidative
effects of statins could play a role in CHF prevention.15

Evidence
indicates that calcific aortic stenosis is the product of an active
inflammatory process. Once established, no known medical therapy exists
that reduces the progression and helps delay the need for aortic valve
replacement. Findings from a study by Novaro et al support the
hypothesis that oxidized LDL-C plays a role in the pathogenesis and
progression of calcific aortic stenosis and indicate that alternative
effects of statin therapy may also be important in modulating the
progression of this condition. Statins decrease monocyte adhesiveness
and plaque calcification, which are important histologic
characteristics of calcific aortic valve disease. Therefore, it is
possible that the anti-inflammatory effects of statins may play a role
in modifying the active subendothelial process that occurs on diseased
aortic valves.16 Kontopoulos et al indicated that the
pleiotropic effects of atorvastatin might play a significant role in
improvement of aortic elasticity via reduction in arterial wall
inflammation and antioxidative effects.17

One
of the observed advantageous results of statin use may be on the
variability of QT dispersion. In a study involving fluvastatin, it was
shown that this drug, besides affecting lipid levels, improved
inhomogeneity of ventricular recovery. This finding may be significant
to patients with cardiac disease who have increased risk for sudden
cardiac death or life-threatening ventricular arrhythmia. Reduction of
sudden cardiac death could possibly contribute to the
mortality-reducing effect of statins.18
 

Stroke
Clinical
trials of statins have demonstrated a reduction in ischemic stroke.
These results may be due to stabilization of atherosclerosis at
vascular sites outside the brain, such as the carotid artery or the
aortic arch. In addition, the antithrombotic properties of statins
decrease plaque disruption and reduce artery to artery thromboembolism.
The statins may also ameliorate a number of pathophysiological
processes that occur during cerebral ischemia and reperfusion through
endothelial effects and inhibition of inflammation. Oxidative injury
appears to be a fundamental mechanism of cerebrovascular disease and
HMG-CoA reductase inhibitors may be neuroprotective through their
antioxidant effects.19
 

Osteoporosis
Inhibition
of protein prenylation has been demonstrated to be the mechanism of
action for the nitrogen-containing bisphosphonates, which affect
osteoclastic bone resorption.20 Statins, therefore, share with bisphosphonates the ability to inhibit osteoclast function and reduce osteoclast number.21
Studies have indicated that there may be an association between regular
use of statin drugs and a decreased bone fracture risk, particularly in
the hip.22 In the study by Wang et al the use of statin
lipid-lowering medication was associated with a 50% reduction in the
risk of hip fracture.23 The Geelong Osteoporosis Study also confirmed that statin use is associated with a reduction in fracture risk.24
Despite the apparent reductions in fracture risk, clinical studies have
found that statin use is associated with only a modest increase in bone
mineral density and inconsistent effects on bone turnover.25
 

Arthritis
Leung
et al documented an antiarthritic effect of statins. In this study it
was demonstrated that simvastatin was effective in treating murine
collagen-induced arthritis (a model for human rheumatoid arthritis) in
mice. These effects are mediated through inhibition of MHC II and a
resulting decrease in T-cell response. The study represents the future
development potential for statin-like drugs due to their
anti-inflammatory activities.26
 

Diabetes
Inflammatory
markers linked with insulin resistance are associated with the
development of type 2 diabetes in adults. The mechanism by which
inflammation leads to glucose intolerance and diabetes is not known,
but proinflammatory cytokines may affect the insulin receptor or impair
insulin action and secretion. Freeman et al examined the development of
diabetes mellitus in men aged 45 to 64 during the West of Scotland
Coronary Prevention Study. Subjects assigned to pravastatin therapy
were concluded to have a 30% reduction in the risk of diabetes. Three
effects of pravastatin therapy were speculated to play a role in the
development of diabetes. First, the triglyceride-lowering effect of
pravastatin therapy could reduce the risk of developing insulin
resistance. However, other lipid-lowering agents do not appear to
improve insulin resistance. Second, pravastatin has been shown to
reduce levels of interleukin 6 and TNF-a through its anti-inflammatory
effects. These cytokines are known to inhibit lipoprotein lipase
activity and to stimulate lipolysis in adipose tissue. Pravastatin may
therefore interrupt the progression from central obesity to insulin
resistance mediated by the adipose tissue-derived cytokines. Third,
impaired endothelial function has been shown to correlate with insulin
resistance. Pravastatin, by restoring endothelial function, may
beneficially affect glucose and insulin transport.27
 

Dementia
Statins hold promise for intervention in both Alzheimer's disease and vascular dementia.28
It is believed that cholesterol plays a pivotal role in the formation
of amyloid plaques, and the reduction of cholesterol formation may slow
the process of plaque formation. It is also possible that statin
antioxidant or anti-inflammatory properties result in cognitive benefit.29
The up-regulation of endothelial nitric oxide synthase augments
cerebral blood flow, which may affect the development of dementia. The
pathology of Alzheimer's disease has also been associated with an
inflammatory glial response to neuronal injury. Therefore, the direct
anti-inflammatory effects of statins could potentially have an impact
in Alzheimer's disease.21
 

Multiple Sclerosis
Multiple
sclerosis is believed to develop when the body's immune cells, led by
helper T cells, attack the myelin sheath around nerve cells. The damage
in the brain and spinal cord results in impaired transmission of nerve
impulses and progressive physical disability.30 Youssef et al31
found atorvastatin to be effective against experimental autoimmune
encephalomyelitis (EAE), an experimentally induced rodent autoimmune
disease that is used as a model of human multiple sclerosis. It did not
just prevent EAE onset but also reduced established disease by
redirecting myelin-specific helper T cells from the destructive role of
causing disease to that of suppressing autoimmunity. However, the
mechanism of T-cell reprogramming remains uncertain.30 In a
study of simvastatin in 30 people with multiple sclerosis, the findings
suggested that an 80-mg daily dose over a six-month period could
inhibit the inflammatory components of the disease which lead to
neurological disability.32
 

Organ Rejection
Because
of their effects of decreasing antibody-dependent cellular cytotoxicity
and natural-killer-cell function, the statins may influence the
development of acute organ rejection. These two mechanisms have been
implicated in the clinical rejection of renal allografts. Also, a study
by Kobashigawa et al concluded that after cardiac transplantation,
pravastatin had beneficial effects on cholesterol levels, the incidence
of rejection causing hemodynamic compromise, one-year survival, and the
incidence of coronary vasculopathy.10
 

Kidney Disease
Theoretically,
statins' anti-inflammatory and immunomodulatory effects and also their
effects on endothelial function may be beneficial in renal
hemodynamics. Research conducted by Tonelli et al suggested that
individuals with moderate to severe kidney disease, especially those
with proteinuria, may derive clinically relevant renal benefit from
pravastatin.33 Usui et al demonstrated that cerivastatin
treatment prevented glomerular injury in diabetic rats independent of
cholesterol-lowering effects.34

Cancer
Cells located in the G1 and G2-M phases of the cell cycle are most sensitive to radiation therapy. The ability of statins to arrest cells in late G1 phase
potentially sensitizes them to radiation. Because HMG-CoA reductase
inhibitors exhibit these effects, numerous clinical trials are under
way to determine if the actions will lead to clinical benefit.2
Li et al showed that attenuation of adaptive cholesterol responses
after exposure to cytotoxic agents such as chemotherapy and radiation
resulted in decreased acute myeloid leukemia cell survival.35
 

Age-Related Maculopathy
Hypercholesterolemia,
oxidative damage, and endothelial dysfunction have been hypothesized as
mechanisms involved in the incidence and progression of age-related
maculopathy. Therefore, via their cholesterol-lowering, antioxidant,
and endothelial effects, statins may reduce the incidence and
progression of age-related maculopathy. However, results of studies in
this area have been inconsistent.36

Sepsis
Sepsis
and septic shock are complex inflammatory syndromes involving multiple
cellular activation processes. Endothelial activation, endothelial
dysfunction, and apoptosis all play significant roles in the
pathogenesis of sepsis and multiorgan dysfunction syndrome. Statins may
exert a protective effect against sepsis through anti-inflammatory
properties.37 Liappis et al compared the mortality and
clinical and laboratory findings of patients taking statins with those
of patients not receiving statins at the time of bacteremic episode.
Overall hospital mortality rates were reduced with statins.38
 

CONCLUSION
Questions
remain about the clinical significance of the statins' pleiotropic
actions. While generally well tolerated, statins have important adverse
effects such as muscle toxicity39 as well as potential for
drug interactions. Future research will determine the role of the
HMG-CoA reductase inhibitors in additional disease states.

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b The Role of Vaccination in the Prevention of Influenza

2.0 Credits, Expires: 12/31/2009 **Payment is required for exam to be graded.

b The Constipation Conundrum: What Now in Chronic Constipation and IBS-C

This activity is supported by an educational grant from Sucampo Pharmaceuticals, Inc and Takeda Pharmaceuticals North America, Inc.

b Mission Possible: Taking CONTROL of Pediatric GERD

This activity is supported by an educational grant from TAP Pharmaceutical Products Inc.

b Newer Insights Into the Prevention of the Common Cold

This activity is supported by an educational grant from Procter & Gamble.

b Advanced Topics in Medicare Part D: Assisting Patients Eligible for Low-Income Subsidies

This activity is supported by an educational grant from UnitedHealthcare.

b Irritable Bowel Syndrome: Update on Medical Management and the Use of Probiotics

This activity is supported by an educational grant from Procter & Gamble, Inc.


















Fluoroquinolone Positioning in Hospital Antimicrobial Stewardship Programs
Sickle Cell Disease
Lead Toxicity














Cinnamon–More Than Just a Flavoring Agent
Nonalzheimer’s Dementias
Temporomandibular Disorders: Review and Management



Posted by Niels P. Mayer in Medicine at 20080107 Comments[1]

Comments:

After reading the current, January issue of Businessweek titled "Do Cholesterol Drugs Do Any Good?" I would never go near these.

It sites people getting side effects such as getting amneisa and horrible muscle cramping..with little benefit.

Grace

Posted by Grace on January 23, 2008 at 07:27 AM PST #

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