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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical
Design
Volume 15, Number 27, 2009
Contents
Drugs Targeting Atherosclerosis: Current
and Emerging Approaches
Executive Editors: Vangelis G. Manolopoulos
and Anna Tavridou
Editorial: Pp. 3091-3093
[PMID:
19754383 PubMed - indexed for MEDLINE]
Anti-Atherosclerotic Molecules Targeting Oxidative Stress
and Inflammation Pp. 3094-3107
A. Adameova, Y.J. Xu, T.A. Duhamel, P.S.
Tappia, L. Shan and N.S. Dhalla
[Abstract] [Purchase
Article]
[PMID:
19754384 PubMed - indexed for MEDLINE]
Rho Kinase: An Important Mediator of
Atherosclerosis and Vascular Disease Pp.
3108-3115
Qian Zhou and James K. Liao
[Abstract] [Purchase
Article]
[PMID:
19754385 PubMed - indexed for MEDLINE]
Inhibitors of the 5-Lipoxygenase Pathway
in Atherosclerosis Pp. 3116-3132
Magnus Bäck
[Abstract] [Purchase
Article]
[PMID:
19754386 PubMed - indexed for MEDLINE]
Prevention of Atherosclerosis by Interference
with the Vascular Nitric Oxide System Pp.
3133-3145
Huige Li and Ulrich Förstermann
[Abstract] [Full
Text Article]
[PMID:
19754387 PubMed - indexed for MEDLINE]
Recent Advances on the Antiatherogenic
Effects of HDL- Derived Proteins and Mimetic Peptides
Pp. 3146-3166
Maria P. Petraki, Polyxeni T. Mantani and
Alexandros D. Tselepis
[Abstract] [Purchase
Article] [PMID:
19754388 PubMed - indexed for MEDLINE]
EP2300 Compounds: Focusing on the Antiatherosclerotic
Properties of Squalene Synthase Inhibitors Pp.
3167-3178
Anna Tavridou and Vangelis G. Manolopoulos
[Abstract] [Purchase
Article]
[PMID:
19754389 PubMed - indexed for MEDLINE]
Oral Antidiabetic Agents: Anti-Atherosclerotic
Properties Beyond Glucose Lowering? Pp.
3179-3192
N. Papanas and E. Maltezos
[Abstract] [Purchase
Article]
[PMID:
19754390 PubMed - indexed for MEDLINE]
Genomics and the Prospects of Existing
and Emerging Therapeutics for Cardiovascular Diseases
Pp. 3193-3206
M. Zaiou, H. Benachour, J.B. Marteau, S.
Visvikis-Siest and G. Siest
[Abstract] [Purchase
Article]
[PMID:
19754391 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
[PMID:
19754383 PubMed - indexed for MEDLINE]
Editorial: Drugs Targeting Atherosclerosis: Current
and Emerging Approaches
Coronary heart disease is the leading cause of morbidity
and mortality worldwide. Atherosclerosis is a common denominator
underlying most clinical manifestations of cardiovascular
disease. It is a complex inflammatory process characterized
by the cross-talk between excessive inflammation and lipid
accumulation. Despite of extensive research, there are several
unmet needs in the management of atherosclerosis. Dyslipidemia
is one of the main risk factors leading to atherosclerosis.
Hitherto, treating hyperlipidemia with the use of statins
is the main pharmacological intervention for prevention of
atherosclerosis-related disorders. Despite significant clinical
benefits associated with statin treatment, monotherapy with
statins is frequently insufficient since the reduction of
the risk for major coronary events is only 30%. Thus, there
is a need for new drugs with different mechanisms of action
to directly inhibit atherosclerosis. Both the accumulating
knowledge of the molecular mechanisms of atherogenesis and
new strategies in drug design and synthesis are expected to
bring about alternative therapeutic options in the treatment
of atherosclerosis-related disorders. Pharmaceutical industry
is either improving existing molecules or synthesizing novel
molecules against new targets aiming at direct inhibition
of atherosclerosis. In addition, several drugs already in
use for cardiovascular and metabolic disorders appear to possess
direct antiatherosclerotic properties due to mechanisms of
action unrelated to their main effects.
We have recently published an overview of all different classes
of novel molecules targeting dyslipidemia and atherosclerosis
[1]. In the present series of articles, some of the most promising
developments in atherosclerosis-related research relevant
to drug development are thoroughly reviewed, including novel
molecules targeting dyslipidemia and atherosclerosis, anti-atherosclerotic
potential of established therapeutic agents for other indications,
as well as recent developments in knowledge of pathophysiologic
pathways related to atherosclerosis.
In the first paper of the present issue, Adameova et al.
[2] review the involvement of inflammation and oxidative stress
in the pathogenesis of atherosclerosis and focus on the mechanisms
of some clinically used as well as potential anti-atherosclerotic
substances with anti-inflammatory and anti-oxidative properties.
These include several drugs that are used as the first line
therapy in dyslipidemia. These agents have been found to exhibit
beneficial effects which are independent of their lipid-modifying
properties. Both statins and fibrates have been reported to
exert anti-inflammatory and anti-oxidative effects in addition
to their main actions. Furthermore, anti-hypertensive, anti-diabetic
and anti-platelet drugs, which reduce oxidative stress and
inflammation, have also been shown to attenuate atherosclerosis.
In addition, novel substances such as HDL-related agents,
cyclopentenone prostaglandins, lipoprotein-associated phospholipase
A2 inhibitors, 5-lipoxygenase pathway inhibitors, acyl CoA:
cholesterol acyltransferase inhibitors, analogues of probucol
and lysophosphatidic acid antagonists have been developed
for the treatment of atherosclerosis as a consequence of their
actions on oxidative stress and inflammation.
In the past few years, compelling evidence suggests that statins
can decrease vascular inflammation and attenuate the development
of atherosclerosis through their so-called “pleiotropic
effects”. These cholesterol-independent effects are
predominantly due to their ability to inhibit isoprenoid synthesis.
In particular, inhibition of geranylgeranylpyrophosphate synthesis
leads to inhibition of Rho and its downstream target, Rho-kinase
(ROCK). Thus, some of the beneficial effects of statin therapy
could be due to inhibitory effects on ROCK. ROCK is involved
in mediating diverse cellular functions such as smooth muscle
contraction, cell migration and proliferation. While increased
ROCK activity is associated with endothelial dysfunction,
cerebral ischemia, coronary vasospasms and metabolic syndrome,
the inhibition of ROCK by statins or selective ROCK inhibitors
leads to up-regulation of endothelial nitric oxide synthase
(eNOS), decreased vascular inflammation, and reduced atherosclerotic
plaque formation. Zhou and Liao, in their contribution to
the present issue, highlight the impact of ROCK in cardiovascular
disease and its contributory role to vascular inflammation
and the atherosclerosis [3].
The 5-lipoxygenase pathway of arachidonic acid metabolism
has gained a lot of attention in trying to explain the relation
of atherosclerosis with inflammation. The inflammatory environment
within the atherosclerotic lesion activates this pathway and
leads to biosynthesis of the potent lipid inflammatory mediators
leukotrienes. The review by Back in this issue [4] summarizes
the structure and function of the enzymes and receptors that
constitute this pathway, and gives an overview of their role
in leukotriene synthesis and signaling. More specifically,
it presents the enzymes 5-lipoxygenase with its activating
protein, FLAP (ALOX5AP), leukotriene A4 hydrolase and leukotriene
C4 synthase, as well as the receptors for leukotriene B4 (BLT1
and BLT2) and cysteinyl-leukotrienes (CysLT1 and CysLT2),
respectively. Furthermore, some of the genetic association
studies implicating a role for the respective protein in atherosclerosis
and cardiovascular risk are reviewed. Finally, the experimental
and clinical findings that relate to atherosclerosis with
leukotriene synthesis inhibitors and leukotriene receptor
antagonists are presented. Overall, inhibition of the 5-lipoxygenase
pathway appears as a promising strategy to inhibit atherosclerosis;
several inhibitors of this pathway are now evaluated in clinical
trials of patients with cardiovascular disease.
A common denominator in many processes involved in atherogenesis
and development of atherosclerosis is endothelial dysfunction.
Nitric oxide (NO) produced by eNOS represents a key molecule
in endothelial dysfunction. The role of NO in atherogenesis
as well as the efforts for prevention of atherosclerosis by
interference with the vascular nitric oxide system are presented
by Li and Förstermann in the next paper of the present
issue [5]. NO bioavailability is decreased in atherosclerosis
due to increased NO inactivation by reactive oxygen species
and reduced NO synthesis. Various types of vascular pathophysiology
are associated with oxidative stress, with NADPH oxidases,
which inactivate NO, being the major source of reactive oxygen
species. Also, oxidative stress is likely to be the main cause
for oxidation of the essential NOS cofactor, tetrahydrobiopterin
(BH4). Based on these pathophysiological
mechanisms, the therapeutic potential of a number of compounds
is discussed in this review: (1) NO donors; (2) L-arginine;
(3) folic acid; (4) BH4 and
its precursor sepiapterin; (5) compounds that upregulate eNOS
and concomitantly maintain eNOS activity (e.g. midostaurin,
betulinic acid, ursolic acid, AVE9488 and AVE3085); (6) compounds
that enhance the de novo synthesis of BH4
by stimulating expression or activity of GTP cyclohydrolase
I; and (7) 3-hydroxy-3-methylgulutaryl-coenzyme A inhibitors
(statins) and drugs interrupting the renin-angiotensin-aldosterone
system. Some more established compounds, including statins,
angiotensin II type 1 receptor blockers, angiotensin-converting
enzyme (ACE) inhibitors, the aldosterone antagonist eplerenone
and the renin inhibitor aliskiren, which enhance NO bioactivity
and reduce atherosclerosis progression through multiple mechanisms,
are also discussed.
As stated earlier, dyslipidemia is one of the major risk factors
leading to atherosclerosis. The availability of statins is
beneficial in reducing levels of total and LDL-cholesterol
and has been exploited in the clinic. However, other components
of cholesterol synthesis and transport could be targeted in
developing useful therapeutic agents. High-density lipoprotein
(HDL) constitutes an attractive such target. The plasma levels
of HDL- cholesterol are inversely correlated with the risk
of atherosclerosis and cardiovascular disease in humans. One
of the major mechanisms whereby HDL particles protect against
atherosclerosis is that of reverse cholesterol transport from
atherosclerotic lesion macrophages to the liver. HDL particles
also appear to have antiatherogenic and cardioprotective actions
by expressing antioxidant, anti-inflammatory, antithrombotic,
and antiapoptotic properties. HDL consists of several subpopulations
of spherical particles that contain lipids and apolipoproteins,
both of which impact on HDL remodeling and metabolism. Differences
in functionality of HDL subpopulations may be important in
the development of new therapies. The paper by Petraki et
al. [6] thoroughly discusses current knowledge on the biological
activities of the major apolipoproteins and enzymes associated
with HDL. Understanding these mechanisms will contribute significantly
to current and future efforts to develop therapeutic strategies
promoting the antiatherogenic potency of HDL.
Another promising target for inhibition of dyslipidemia-related
atherosclerosis, which has received little attention so far,
is squalene synthase. The pathways for synthesis of non-sterol
products diverge from the synthesis of cholesterol either
at or before the farnesyl pyrophosphate branch point. Squalene
synthase catalyzes the conversion of two molecules of farnesyl
pyrophosphate to squalene in a two-step reaction, the first
committed step in de novo cholesterol biosynthesis.
Therefore, inhibitors of squalene synthase are candidate hypocholesterolemic
agents because they decrease circulating LDL-cholesterol by
an increased expression of hepatic LDL receptors in a similar
manner to statins. Also, depending on their structure, they
may exhibit a range of antiatherosclerotic properties independent
of their hypolipidemic properties.The paper by Tavridou and
Manolopoulos [7], following a brief introduction to different
classes of squalene synthase inhibitors and representative
molecules, presents the accumulating preclinical in vitro
and in vivo experimental evidence relevant to squalene synthase
inhibitors EP2306 and EP2302 and discusses their properties.
Both compounds seem to have a similar inhibitory effect in
the progression of atherosclerosis in the cholesterol-fed
rabbit. Treatment with EP2300 compounds did not adversely
affect liver transaminases or cause toxicity on various organs
of this animal model. The satisfactory preclinical safety
profile of EP2300 compounds in this animal model is a promising
finding in view of future clinical studies.
In addition to novel anti-atherosclerotic agents, a lot of
attention has been focused lately on the anti-atherosclerotic
potential of established therapeutic agents for other indications,
most notably diabetes. Type 2 diabetes is associated with
substantially increased cardiovascular mortality and atherosclerosis.
The need to reduce the progression of atherosclerosis alongside
lowering blood glucose levels in diabetic patients is now
well established. Ideally, pharmaceutical treatment should
address both of these needs. The paper by Papanas and Maltezos
[8] presents the accumulating evidence of anti-atherosclerotic
effects exerted by oral antidiabetic agents currently in clinical
use. Metformin has so far consistently succeeded in reducing
cardiovascular morbidity and mortality and exerting beneficial
effects on lipids. From the new agents, the thiazolidinediones
rosiglitazone and pioglitazone have been most widely studied.
They have a favourable effect on fat distribution and improve
lipid profile, fibrinolysis and endothelial function. Moreover,
they reduce blood pressure and inflammatory markers, attenuate
the progression of carotid intima-media thickness (CIMT) and
may reduce the rates of coronary restenosis following percutaneous
coronary intervention. Finally, emerging experimental and
clinical evidence for anti-atherosclerotic effects of meglitinides
(repaglinide and nateglinide) and acarbose is reviewed. Interestingly,
some of the beneficial effects of antidiabetic agents appear
to be independent of their glucose-lowering action. Thus,
oral antidiabetic agents are now emerging as useful tools
for the attenuation of the atherosclerotic activity and for
the protection of the vasculature in patients with type 2
diabetes.
It is well established that atherosclerosis is a complex multifocal
disease resulting from the interaction of various genetic
and environmental factors. Recent advances in molecular genetics
have started shedding light into the role of genetic polymorphisms
in pathogenesis of atherosclerotic-related diseases. This
growing knowledge about genetic influence on cardiovascular
diseases combined with the recently generated large amounts
of genomic data hold promise for identification of novel drug
targets as well as new markers for atherosclerotic cardiovascular
disease. In the final paper of this issue, Zaiou et al [9]
discuss these issues. Cardiovascular pharmacogenomics have
now the potential for leading to identification of genetic
contributors and therefore to development of predictive genetic
tests that could optimize drugs efficacy and minimize toxicity.
For example, clinical studies have shown that genetic variations
within cytochromes P450 (CYPs), 3-Hydroxyl-3-Methylglutaryl
Coenzyme A Reductase (HMGCR) and apolipoprotein E
(APOE) genes influence individual’s response
to lipid lowering statins. Furthermore, the authors present
an array of molecules that could have pharmacological benefit
for the treatment of atherosclerosis.
In conclusion, there is a need for therapies against atherosclerosis.
Recently, several new targets for dyslipidemia and atherosclerosis
have been discovered. Compounds acting on these targets are
under clinical development but none of these drugs has reached
the market so far. Novel approaches against atherosclerosis
have proven to be difficult to develop, mostly due to toxicity.
Compounds with new mechanisms of action will have to show
benefit compared with statins in major coronary events. Currently,
control of modifiable risk factors and appropriate use of
existing drugs that target atherosclerosis indirectly or in
addition to their main effect should be employed to prevent
cardiovascular disease. Within the next 5 to 10 years however,
it is expected that some of the compounds currently in development
will reach the patient, hopefully reducing atherosclerosis-related
disease burden.
REFERENCES
[1] Tavridou A, Manolopoulos VG. Novel molecules targeting
dyslipidemia and atherosclerosis. Cur Med Chem 2008; 15: 792-802.
[2] Adameova A, Xu YJ, Duhamel TA, Tappia PS, Shan L, Dhalla
NS. Anti-atherosclerotic molecules targeting oxidative stress
and inflammation. Curr Pharm Des 2009; 27: 3094-3107.
[3] Zhou Q, Liao JK. Rho Kinase. An important mediator of
atherosclerosis and vascular disease. Curr Pharm Des 2009;
27: 3108-3115.
[4] Bäck M. Inhibitors of the 5-lipoxygenase pathway
in atherosclerosis. Curr Pharm Des 2009; 27: 3116-3132.
[5] Li H, Förstermann U. Prevention of atherosclerosis
by interference with the vascular nitric oxide system. Curr
Pharm Des 2009; 27: 3133-3145.
[6] Petraki MP, Mantani PT, Tselepis AD. Recent advances on
the antiatherogenic effects of HDL-derived proteins and mimetic
peptides. Curr Pharm Des 2009; 27: 3146-3166.
[7] Tavridou A, Manolopoulos VG. EP2300 compounds: focusing
on the antiatherosclerotic properties of squalene synthase
inhibitors. Curr Pharm Des 2009; 27: 3167-3178.
[8] Papanas N, Maltezos E. Oral antidiabetic agents: anti-atherosclerotic
properties beyond glucose lowering? Curr Pharm Des 2009; 27:
3179-3192.
[9] Zaiou M, Benachour H, Marteau JB, Visvikis-Siest S, Siest
G. Genomics and the prospects of existing and emerging therapeutics
for cardiovascular disease. Curr Pharm Des 2009; 27: 3193-3206.
Vangelis G. Manolopoulos and Anna Tavridou
Laboratory of Pharmacology,
Medical School,
Democritus University of Thrace,
Alexandroupolis,
Greece
[Back to top]
[Purchase Article] [PMID:
19754384 PubMed - indexed for MEDLINE]
Anti-Atherosclerotic Molecules Targeting Oxidative Stress
and Inflammation
A. Adameova, Y.J. Xu, T.A. Duhamel, P.S.
Tappia, L. Shan and N.S. Dhalla
The accumulation of lipids within arteries remains to
be the initial impulse for the pathogenesis of atherosclerosis;
however, both inflammation and oxidative stress are considered
to play a critical role in this process. Several lipid lowering
drugs are used as the first line therapy in atherosclerosis;
however, different agents have been found to exhibit beneficial
effects which are independent of their lipid lowering activity.
Both statins and fibrates have been reported to exert anti-inflammatory
and anti-oxidative effects in addition to their anti-atherosclerotic
actions. Furthermore, anti-hypertensive, anti-diabetic and
anti-platelet drugs, which reduce oxidative stress and inflammation,
have been shown to attenuate atherosclerosis. In addition,
novel substances such as HDL-related agents, cyclopentenone
prostaglandins, lipoprotein-associated phospholipase A2
inhibitors, 5-lipoxygenase pathway inhibitors, acyl CoA: cholesterol
acyltransferase inhibitors, analogues of probucol and lysophosphatidic
acid antagonists have been developed for the treatment of
atherosclerosis as a consequence of their actions on oxidative
stress and inflammation. The present article reviews the involvement
of inflammation and oxidative stress in the pathogenesis of
atherosclerosis and focuses on the mechanisms of some clinically
used as well as potential anti-atherosclerotic substances
with anti-inflammatory and anti-oxidative properties.
[Back to top]
[Purchase Article] [PMID:
19754385 PubMed - indexed for MEDLINE]
Rho Kinase: An Important Mediator of Atherosclerosis and Vascular
Disease
Qian Zhou and James K. Liao
Atherosclerosis is a complex inflammatory process characterized
by the cross-talk between excessive inflammation and lipid
accumulation. In the past few years, compelling evidence suggests
that statins can decrease vascular inflammation and attenuate
the development of atherosclerosis through their so-called
“pleiotropic effects”. These cholesterol-independent
effects are predominantly due to their ability to inhibit
isoprenoid synthesis. In particular, inhibition of geranylgeranylpyrophosphate
synthesis leads to inhibition of Rho and its downstream target,
Rho-kinase (ROCK). Thus, one of the beneficial effects of
statin therapy could be due to inhibitory effects on ROCK.
ROCK is involved in mediating diverse cellular functions such
as smooth muscle contraction, cell migration and proliferation.
While increased ROCK activity is associated with endothelial
dysfunction, cerebral ischemia, coronary vasospasms and metabolic
syndrome, the inhibition of ROCK by statins or selective ROCK
inhibitors leads to up-regulation of endothelial nitric oxide
synthase (eNOS), decreased vascular inflammation, and reduced
atherosclerotic plaque formation. This review will focus on
the impact of ROCK in cardiovascular disease and its contributory
role to vascular inflammation and the atherosclerosis.
[Back to top]
[Purchase Article] [PMID:
19754386 PubMed - indexed for MEDLINE]
Inhibitors of the 5-Lipoxygenase Pathway in Atherosclerosis
Magnus Bäck
The inflammatory environment within the atherosclerotic
lesion stimulates the 5-lipoxygenase pathway of arachidonic
acid metabolism, leading to the biosynthesis of the potent
lipid inflammatory mediators leukotrienes. The present review
summarizes the components of this pathway; the enzymes 5-lipoxygenase
(5-LO, ALOX5) with its activating protein, FLAP (ALOX5AP),
LTA4 hydrolase and LTC4
synthase, as well as the receptors for leukotriene B4
(BLT1 and BLT2)
and cysteinyl-leukotrienes (CysLT1
and CysLT2), respectively.
Genetic variations within the genes encoding these proteins
have been associated with cardiovascular risk. Inhibiting
the 5-lipoxygenase pathway through either leukotriene synthesis
inhibitors or leukotriene receptor antagonists in experimental
models of atherosclerosis has however generated contradictory
results. Several inhibitors of the 5-lipoxygenase pathway
are now evaluated in clinical trials of patients with cardiovascular
disease.
[Back to top]
[Full
Text Article]
[PMID:
19754387 PubMed - indexed for MEDLINE]
Prevention of Atherosclerosis by Interference with the Vascular
Nitric Oxide System
Huige Li and Ulrich Förstermann
Nitric oxide (NO) produced by endothelial NO synthase
(eNOS) represents an anti-atherosclerotic principle. NO bioavailability
is decreased in atherosclerosis due to increased NO inactivation
by reactive oxygen species and reduced NO synthesis. Various
types of vascular pathophysiology are associated with oxidative
stress, with NADPH oxidases as the major source of reactive
oxygen species. These inactivate NO. Also, oxidative stress
is likely to be the main cause for oxidation of the essential
NOS cofactor, tetrahydrobiopterin (BH4).
A lack of BH4 leads to eNOS
uncoupling (i.e., uncoupling of oxygen reduction from NO synthesis
in eNOS). Based on these pathomechanisms, the therapeutic
potential of a number of compounds is discussed in this review:
(1) NO donors; (2) L-arginine; (3) folic acid; (4) BH4
and its precursor sepiapterin; (5) compounds that upregulate
eNOS and concomitantly maintain eNOS activity (e.g. midostaurin,
betulinic acid, ursolic acid, AVE9488 and AVE3085); (6) compounds
that enhance the de novo synthesis of BH4
by stimulating expression or activity of GTP cyclohydrolase
I; and (7) 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors
(statins) and drugs interrupting the renin-angiotensin-aldosterone
system. Statins, angiotensin II type 1 receptor blockers,
angiotensin-converting enzyme (ACE) inhibitors, the aldosterone
antagonist eplerenone and the renin inhibitor aliskiren enhance
NO bioactivity and reduce atherosclerosis progression through
multiple mechanisms.
[Back to top]
[Purchase Article] [PMID:
19754388 PubMed - indexed for MEDLINE]
Recent Advances on the Antiatherogenic Effects of HDL- Derived
Proteins and Mimetic Peptides
Maria P. Petraki, Polyxeni T. Mantani and
Alexandros D. Tselepis
The plasma levels of high-density lipoprotein (HDL) cholesterol
are inversely correlated with the risk of atherosclerosis
and cardiovascular disease (CVD) in humans. One of the major
mechanisms whereby HDL particles protect against atherosclerosis
is that of reverse cholesterol transport from atherosclerotic
lesion macrophages to the liver. HDL particles also exhibit
various antiatherogenic and cardioprotective effects by modulating
the function of various cells including the cells of the artery
wall and by expressing antioxidant, anti-inflammatory, antithrombotic
and antiapoptotic effects. Most these effects are mediated
by various lipid and protein HDL components. A plethora of
studies have been conducted in order to shed light on the
mechanisms by which each HDL component contributes to the
functionality of this lipoprotein. The complete elucidation
of these mechanisms will significantly contribute to current
efforts focused on the development of therapeutic strategies
to promote the antiatherogenic potency of HDL. The present
review discusses current knowledge on the biological activities
of the major apolipoproteins and enzymes associated with HDL,
which may significantly contribute to the overall antiatherogenic
and cardioprotective effects of this lipoprotein.
[Back to top]
[Purchase Article] [PMID:
19754389 PubMed - indexed for MEDLINE]
EP2300 Compounds: Focusing on the Antiatherosclerotic Properties
of Squalene Synthase Inhibitors
Anna Tavridou and Vangelis G. Manolopoulos
Although treatment with statins significantly reduces
adverse cardiovascular outcomes, several studies have shown
that cardiovascular events continue to occur in two thirds
of all patients. A logical pharmacologic approach to further
reduce cardiovascular disease mortality should be focused
on direct modifiers of atherosclerosis or lipid-modifying
agents with different mechanism of action than existing drugs
against dyslipidemia. Squalene synthase inhibitors can decrease
circulating low-density lipoprotein (LDL)-cholesterol by an
increased expression of hepatic LDL receptors in a similar
manner to statins. Also, depending on their structure, they
may possess antiatherosclerotic properties independent of
their lipid-modifying effects. This review, following a brief
introduction to different classes of squalene synthase inhibitors
and representative molecules, presents the accumulating in
vitro and in vivo experimental evidence relevant
to squalene synthase inhibitors EP2306 and EP2302 and discusses
their properties. EP2306 and EP2302 show a similar inhibitory
effect in the progression of atherosclerosis in the cholesterol-fed
rabbit. Moreover, EP2306 showed a significant long-term antiatherosclerotic
effect not shared by simvastatin or their combination in this
animal model. EP2302 also showed a favorable effect in the
regression of pre-established atherosclerotic lesions. It
is reasonable to hypothesize that EP2302, due to its NO-releasing
and enhancing properties, could have additional advantages
compared to EP2306. Treatment with EP2300 compounds did not
adversely affect liver transaminases or cause toxicity on
various organs of the cholesterol-fed rabbit. The satisfactory
safety profile of EP2300 compounds in this animal model is
a promising finding in view of future clinical studies.
[Back to top]
[Purchase Article] [PMID:
19754390 PubMed - indexed for MEDLINE]
Oral Antidiabetic Agents: Anti-Atherosclerotic Properties
Beyond Glucose Lowering?
N. Papanas and E. Maltezos
Type 2 diabetes is associated with substantially increased
cardiovascular mortality. The need to reduce the progression
of atherosclerosis alongside lowering blood glucose levels
is now well established. Ideally, pharmaceutical treatment
should address both of these needs. This review summarises
current evidence of the anti-atherosclerotic effects exerted
by oral antidiabetic agents. Metformin has so far consistently
succeeded in reducing cardiovascular morbidity and mortality
and exerting beneficial effects on lipids. Of the new agents,
thiazolidinediones (rosiglitazone and pioglitazone) have been
most widely studied. They have a favourable effect on fat
distribution and improve lipid profile, fibrinolysis and endothelial
function. Moreover, they reduce blood pressure and inflammatory
markers, attenuate the progression of carotid intima-media
thickness (CIMT) and may reduce the rates of coronary restenosis
following percutaneous coronary intervention. Glinides (repaglinide
and nateglinide) have also been documented to improve endothelial
function and lipid profile, to reduce oxidative stress, platelet
activity and inflammatory markers, and to diminish the progression
of CIMT. Finally, acarbose may significantly reduce new cases
of hypertension and cardiovascular events, as well as diminishing
the progression of CIMT in patients with impaired glucose
tolerance. Interestingly, some of these beneficial effects
appear to be independent of the antidiabetic action. Thus,
oral antidiabetic agents are now emerging as useful tools
for the attenuation of the atherosclerotic activity and for
the protection of the vasculature in patients with type 2
diabetes.
[Back to top]
[Purchase Article] [PMID:
19754391 PubMed - indexed for MEDLINE]
Genomics and the Prospects of Existing and Emerging Therapeutics
for Cardiovascular Diseases
M. Zaiou, H. Benachour, J.B. Marteau, S.
Visvikis-Siest and G. Siest
The growing knowledge about genetic influence on cardiovascular
diseases (CVD) combined with the recently generated amounts
of genomic data hold promise to the identification of new
markers for atherosclerotic CVD. Cardiovascular pharmacogenomics
and pharmacogenetics have now the potential for leading to
identification of genetic contributors and therefore to the
development of predictive genetic tests that could optimize
drugs efficacy and minimize toxicity. Clinical studies have
shown that genetic variations within cytochromes P450 (CYPs),
3-Hydroxyl-3-Methylglutaryl Coenzyme A Reductase (HMGCR)
and apolipoprotein E (APOE) genes influence individual’s
response to lipid lowering statins. Furthermore, development
of antagonists or inhibitors of molecules such as peroxisome
proliferator-activated receptors (PPARs), lipoprotein-associated
phospholipase A2 (Lp-PLA2),
angiotensin-converting enzyme (ACE), angiotensin receptors
and tumor necrosis factor (TNF)-alpha could be another alternative
to prevent atherosclerosis. In addition, novel molecules under
the name of biologics including family of peptides such as
atrial natriuretic peptide (ANP) and brain natriuretic peptide
(BNP), urocortin, apelin and antimicrobial peptides (AMPs)
could be considered as new targets for the prevention and
treatment of CVD.
In this article, we will focus mainly on recent genomic advances
in the development of new markers and therapeutic agents for
CVD. We present an array of molecules that could have pharmacological
benefit for the treatment of heart disease. We also discuss
in details new strategies including biologics, which are actually
the focus of companies for clinical development of therapeutic
drugs. All these efforts provide optimism and attractive promise
to cure CVD.
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