Current Drug Targets - Cardiovascular & Haematological Disorders, Volume 5, Number 2, 2005
Contents
Statins: Effects Beyond Cholesterol Lowering
Guest Editor: Garry X. Shen
Editorial
Garry X. Shen
Statins and Thrombin Pp.115-120
J.W. Fenton II,
D.V. Brezniak, F.A. Ofosu, G.X. Shen, J.R. Jacobson, J.G.N.Garcia
Mechanisms for Antiplatelet
Action of Statins
Pp.121-126
Luca Puccetti, Anna Laura Pasqui, Alberto Auteri and Fulvio Bruni
Cholesterol-independent
Effects of Statins in Inflammation, Immunomodulation and Atherosclerosis Pp.127-134
Claire Arnaud, Niels R. Veillard and Francois Mach
Statin-induced Vascular Smooth
Muscle Cell Apoptosis: A Possible Role in the Prevention of Restenosis? Pp.135-144
Wolfgang Erl
Three’s Company: Regulation
of Cell Fate by Statins Pp.145-163
Joannis E.
Vamvakopoulos
The Role of Statins in
Oxidative Stress and Cardiovascular Disease Pp.165-175
Dominic S. Ng
General Articles
Biological Properties of
Baicalein in Cardiovascular System Pp.177-184
Yu Huang,
Suk-Ying Tsang, Xiaoqiang Yao and Zhen-Yu Chen
Common Therapeutic
Strategies in the Management of Sexual Dysfunction and Cardiovascular Disease Pp.185-195
T.M. Hale, J.L.
Hannan, J.P.W. Heaton, and M.A. Adams
Abstracts
[Back to top] Editorial
Garry X. Shen
Introduction
Within last 30 years, 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase
inhibitors (statins) have become one of the most common classes of prescripted
drugs in routine clinical practice. The original purpose for developing statins
was to reduce cholesterol synthesis. All available statins are able to inhibit
the activity of HMG-CoA reductase, a rate limiting cholesterol synthetic
enzyme, which directly results in decreased generation of mevalonate from
acetyl CoA. Mevalonate is a precursor of a group of active intracellular
mediators (farnesyl and geranyl pyrophosphates) in addition to cholesterol [1].
Treatment with statins not only reduces the levels of cholesterol in the body,
but also affects a variety of biological activities which are either dependent
on or independent to cholesterol lowering. Results from a recent meta-analysis
demonstrated that statin-treatment significantly reduced coronary events by
27%, stroke by 18%, and all-causes mortality by 15% compared to placebo
controls [2]. The beneficial effects of statins have also been seen in
hypercholesterolemic patients with diabetes or hypertension, and even those
with normal cholesterol levels [3]. Accumulating lines of evidence demonstrated
that statin-treatment is helpful in the management of a wide range of
pathological conditions, including thrombotic, inflammatory, autoimmune, and
neurodegenerative diseases as well as organ transplantation, in addition to
atherosclerotic cardiovascular diseases. This hot topic issue aims to help in
the translation of our current knowledge of statins and the expanded clinical
applications of statins.
Coagulation, fibrinolysis and platelet activation
Thrombosis at sites of atherosclerotic lesion formation is the most
common cause of acute coronary syndromes, the leading cause of morbidity and
mortality in North America [4]. A number of studies have examined the effects
of statins on markers of coagulation, fibrinolysis and platelet activation in
experimental or clinical studies. In hypercholesterolemic or diabetic patients
receiving statins, reduced levels of tissue factor, fibrinogen, prothrombin
fragments 1 and 2 (F1+2), tissue plasminogen activator, plasminogen activator
inhibitor-1 (PAI-1) or platelet aggregation have been detected after the
treatment [5-8]. The changes in many of the coagulationor fibrinolysis-related
factors do not correlate with the reduction of cholesterol by statins [7]. In a
recent study in our group, correlations between total or low density
lipoprotein-cholesterol with the levels of PAI-1, but not F1+2, have been
observed in type 2 diabetic patients treated with simvastatin [8]. The findings
suggest that some of anti-thrombotic activities of statins may be secondary to
the cholesterol lowering effects of statins at least in certain populations.
The effects of statins on coagulation or fibrinolytic factors have not been
verified in large-scale clinical trials to our knowledge. The mechanism for
statin-induced anti-thrombotic effects also remains uncertain. Preliminary
studies suggest that Ras and other prenylated proteins, including Rho, Rac and
Rap, may be implicated in statins mediated biological processes [9-11], which
possibly contribute to changes in the regulation of coagulation/fibrinolytic
and thrombotic factors associated with statin treatment. Relevant progresses in
this field have been summarized in the reviews by Dr. J.W. Fenton et al.
and Dr. L. Puccette et al. in following sections of this issue.
Inflammation and immunomodulation
A recent meta-analysis has demonstrated that the most consistent and
significant effects of statins on non-lipid serum markers is a decrease of
C-reactive protein (CRP) [7]. CRP is an acute phase reactant synthesized in the
liver. The levels of CRP in blood circulation have been considered as an
integrated assessment of the activation of inflammation system in the body
[12]. Although the biological activity of CRP remains unclear, the level of CRP
using highly sensitive analyses has been considered as a reliable predicator
for cardiovascular prognosis [13]. Inflammation plays a central role in
atherogenesis [14]. The production of CRP is regulated by cytokines,
particularly interleukin-6 (IL-6). Statins affects signaling pathway of IL-6
through suppressing isoprenylation of Rac-1 [15], which may affect the
formation of CRP. Statins also regulate the expression of major
histocompatibility complex II (MHC-II). MHC-II plays a crucial role in
T-cell-mediated immunomodulation and the pathogenesis of autoimmune disease and
transplantation rejection [16]. Recent studies has demonstrated that statins
are potential treatment for multiple sclerosis and neurodegenerative disease
[17,18]. More autoimmune and inflammation-related diseases are expected to be
beneficial by statin treatment. Dr. F. Mach and his colleagues have highlighted
the recent progresses on the impact of statins on inflammation and
immunomodulation in this issue.
Cell growth and apoptosis
Multiple lines of evidence suggest that statin-treatment inhibits cell
proliferation and promotes apoptosis. Smooth muscle cell (SMC) proliferation is
one of major pathological findings in progressive atherosclerotic plaques as
well as restenosis. Restenosis occurs in 20-40% of patients received
angioplasty or stent [19]. Statin treatment has the potential to reduce the
development of atherosclerosis plaque or stenosis. This hypothesis remains to
be confirmed by experimental and clinical studies. Anti-proliferation effects
of statins have been found in SMC, endothelial cells, fibroblasts and myoblasts
[20]. Inhibition of cell growth or increase in apoptosis in atherosclerotic or
restenotic lesions will be beneficial to the management of ischemic heart
disease. A retrospective study has demonstrated that statin treatment was
associated with lower rates of choroidal neovascularization among patients with
age-related macular degeneration in elders [21]. However, the findings on the
effects of statins on cell proliferation or apoptosis have not been consistent
in previous studies. Effects of statins on cancers remain inconclusive [22].
Relevant progress in this field has been reviewed by Dr. W. Erl and J.
Vamvakopoulos.
Oxidative stress and metabolic syndrome
Oxidative stress causes tissue injury and also mediates the effects of
several biological activators in cells. Dyslipidemia, hyperglycemia, obesity and
angiotension II increase endogenous oxidative stress in tissues through
enhancing the generation of reactive oxygen species (ROS) [23]. ROS plays an
important role in the crosslink between the components of metabolic syndrome
(diabetes, hypertension, obesity and dyslipidemia). Statin treatment reduces
the activities of enzymes mediating the generation of ROS or their metabolism,
which reduces endogenous oxidative stress [24]. Angiotensin II is a key
mediator for the development of hypertension and increases the production of
ROS in the body. The biological activity of angiotensin II is mainly mediated
through its receptor (AT1). Statins down-regulate the density of AT1 in
platelets in hypercholesterolemic patients, ameliorates their dyslipidemia and
helps to control high blood pressure [25]. Statin treatment has been proposed
for use in diabetic patients with and without hypercholesterolemia [26]. A
review provided by Dr. D. Ng provides an update on recent progress in this
field.
Non-LDL-cholesterol lipids
Statins not only reduces the levels of cholesterol, but also the levels
of triglycerides in blood circulation. Moderate increases of HDL-cholesterol
(5-15%) have been observed in trials of statin treatment [27,28]. These
findings imply that the lipid effects of statins are not limited to cholesterol
or LDL-cholesterol lowering. The mechanism for non-cholesterol lowering effects
on lipoproteins and atherogenesis remains to be determined. The levels of
HDL-cholesterol independently correlate to extent of atherosclerotic lesions
detected by angiography [29,30]. The moderate increases in HDL-cholesterol by
statins may have meaningful impact on the development of atherosclerosis. HDL
reduces the susceptibility of LDL to oxidation. The antioxidant effect of HDL
partially results from paraoxonase (PON) associated with HDL. A recent study
has demonstrated that simvastatin upregulated the expression of PON1 in HepG2
hepatocyptes [31]. Increases of triglyceride-rich lipoproteins are evident in
diabetic patients or patients with metabolic syndrome. Growing evidence
suggests that patients with hypertriglyceridemia associated with metabolic
syndrome have increased risk for or ischemic heart disease [32]. Although
statin-treatment has effectively decreased triglyceride levels in
hypercholesterolemic and diabetic patients [33], clinical benefits of
statin-induced triglyceride lowering have mainly been seen in individuals with
high baseline levels [34]. Triglyceride-lowering as well as HDL-rising effects
of statins likely plays important role in the beneficial effects of statins in
patients with cardiovascular diseases and diabetes.
Safety concerns for statin treatment
Low incidence of adverse effects have been described in large-scale
clinical trials using statins. The major adverse effects of statins are
myotoxicity and moderate liver toxicity. Fatal rhadomyolysis associated with
statins is less than one death per million prescriptions of all statins, except
cerivastatin. Cerivastatin has been withdrawn from market in 2001 for this
complication. The majority of myotoxicity caused by statins were related to
drug/drug interference with the P450 system [35]. A meta-analysis of liver
toxicity of statins indicated that low doses of pravastatin, simvastatin and
lovastatin did not increase the rates of liver function abnormalities compared
to placebo in 13 trials [36]. Non-life threatening side effects of statins may
occur in up to 15% of receivers, including mood alterations [35]. Statin
treatment has been considered as safe in general. Limited side effects may be
reduced to minimal by avoiding drug/drug interference.
Conclusion and Perspectives
Statin treatment effectively lowers cardiovascular risks in hyper- and
normocholesterolemic individuals with ischemic heart disease, hypertension,
diabetes, nephrotic disease, and may improve the outcome of autoimmune diseases
or organ transplantation. The beneficial effects of statins may be mediated via
multiple mechanisms including cholesterol lowering, regulation of the coagulation/fibrinolysis
balance, platelet inactivation, inhibition of inflammation, immunomodulation,
anti-oxidative effects, reduced cell proliferation and improved endothelial
function. The excellent safety profile allows statins to be used as primary
and/or secondary intervention agents. Further researches on non-cholesterol
lowering effects of statins are expected to expand their growing clinical
applications.
Acknowledgements
The author is grateful to Drs. J.W. Fenton II, F.A. Ofosu, S. Luwig, H.
te Vethuis, and Mr. S. Nelson for their helps in relevant studies, and grant
supports from Canadian Institute of Health Reseaarch and from Canadian Diabetes
Association.
References
Witiak, D.T., Kuwano, E., Feller, D.R., Baldwin, J.R., Newman, H.A.,
Sankrappa, S.K. Synthesis and antilipidemic properties of cis-7-chloro-3a,
8b-dihydro-3a-methylfuro[3,4-b]benzofuran-3(1H)-one, a tricyclic clofibrate
related lactone having a structural resemblance to mevalonolactone. J. Med.
Chem. 1976, 19, 1214-1220.
Cheung, B.M., Lauder, I.J., Lau, C.P., Kumana, C.R. Meta-analysis of
large randomized controlled trials to evaluate the impact of statins on
cardiovascular outcomes. Br. J. Clin. Pharmacol. 2004, 57, 640-651.
Corsini, A. The safety of HMG-CoA reductase inhibitors in special
populations at high cardiovascular risk. Cardiovasc. Drugs Ther. 2003, 17,
265-285.
Fischer, A., Gutstein, D.E., Fuster, V. Thrombosis and coagulation
abnormalities in the acute coronary syndromes. Cardiol. Clin. 1999, 17,
283-294.
Ferro, D., Basili, S., Alessandri, C., Mantovani, B., Cordova, C.,
Violi, F. Simvastatin reduces monocyte-tissue-factor expression type IIa
hypercholesterolaemia. Lancet. 1997, 25, 350:1222.
Davignon, J. Beneficial cardiovascular pleiotropic effects of statins.
Circulation. 2004, 109(Suppl 1), III39-43.
Balk, E.M., Lau, J., Goudas, L.C., Jordan, H.S., Kupelnick, B., Kim,
L.U., Karas, R.H. Effects of statins on nonlipid serum markers associated with
cardiovascular disease: a systematic review. Ann. Intern. Med. 2003,139, 670-682.
Ludwig, S., Dharmalingam, S., Erickson-Nesmith, S., Ren, S., Zhu, F.,
Ma, G.M., Zhao, R., Fenton, J.W. II, Ofosu, F.A., te Velthuis, H., van Mierlo,
G., Shen, G.X. Simvastatin reduces plasma levels of prothrombin fragement 1 + 2
and plasminogen activator inhibitor-1 in type 2 diabetes mellitus. Can. J.
Diabetes. 2004, 28, 286 (abstract).
van Nieuw Amerongen, G.P., van Delft, S., Vermeer, M.A., Collard, J.G.,
van Hinsbergh, V.W. Activation of RhoA by thrombin in endothelial hyperpermeability:
role of Rho kinase and protein tyrosine kinases. Circ. Res. 2000, 87, 335-340.
[10]. Takemoto, M., Liao, J.K. Pleiotropic effects of
3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler.
Thromb. Vasc. Biol. 2001, 21, 1712-1719.
Comparato, C., Altana, C., Bellosta, S., Baetta, R., Paoletti, R.,
Corsini, A. Clinically relevant pleiotropic effects of statins: drug properties
or effects of profound cholesterol reduction? Nutr. Metab. Cardiovasc. Dis.
2001, 111, 328-343.
Rosalki, S.B. C-reactive protein. Int. J. Clin. Pract. 2001, 55,
269-270.
Ridker, P.M. Cardiology Patient Page. C-reactive protein: a simple test
to help predict risk of heart attack and stroke. Circulation. 2003, 108,
e81-85.
Libby, P. Inflammation in atherosclerosis. Nature. 2002, 420, 868-874.
McCarty, M.F. Reduction of serum C-reactive protein by statin therapy
may reflect decreased isoprenylation of Rac-1, a mediator of the IL-6 signal
transduction pathway. Med. Hypotheses. 2003, 60, 634-639.
Mach, F. Statins as immunomodulatory agents. Circulation. 2004, 109,
II15-17.
Baker, D., Adamson, P., Greenwood, J. Potential of statins for the
treatment of multiple sclerosis. Lancet Neurol. 2003, 2, 9-10.
Stuve, O., Youssef, S., Steinman, L., Zamvil, S.S. Statins as potential
therapeutic agents in neuroinflammatory disorders. Curr. Opin. Neurol. 2003,
16, 393-401.
Johansen, O., Abdelnoor, M., Brekke, M., Seljeflot, I., Hostmark, A.T.,
Arnesen, H. Predictors of restenosis after coronary angioplasty. A study on demographic
and metabolic variables. Scand. Cardiovasc. J. 2001, 35, 86-91.
Negre-Aminou, P., van Vliet, A.K., van Erck, M., van Thiel, G.C., van
Leeuwen, R.E., Cohen, L.H. Inhibition of proliferation of human smooth muscle
cells by various HMG-CoA reductase inhibitors; comparison with other human cell
types. Biochim. Biophys. Acta. 1997, 1345, 259-268.
Wilson, H.L., Schwartz, D.M., Bhatt, H.R., McCulloch, C.E., Duncan,
J.L. Statin and aspirin therapy are associated with decreased rates of
choroidal neovascularization among patients with age-related macular
degeneration. Am. J. Ophthalmol. 2004, 137, 615-624.
Jakobisiak, M., Golab, J. Potential antitumor effects of statins
(Review). Int. J. Oncol. 2003, 3, 055-1069
Strawn, W.B., Ferrario, C.M. Mechanisms linking angiotensin II and
atherogenesis. Curr. Opin. Lipidol. 2002, 13, 505-512. Wassmann, S., Laufs, U.,
Baumer, A.T., Muller, K., Ahlbory, K., Linz, W., Itter, G., Rosen, R., Bohm,
M., Nickenig, G. HMG-CoA reductase inhibitors improve endothelial dysfunction in
normocholesterolemic hypertension via reduced production of reactive oxygen
species. Hypertension. 2001, 37, 1450-1457. Comparato, C., Altana, C.,
Nickenig, G., Baumer, A.T., Temur, Y., Kebben, D., Jockenhovel, F., Bohm, M.
Statin-sensitive dysregulated AT1 receptor function and density in
hypercholesterolemic men. Circulation. 1999, 100, 2131-2134. Ullom-Minnich, P.
Strategies to reduce complications of type 2 diabetes. J. Fam. Pract. 2004, 53,
366-375.
Kjekshus, J., Pedersen, T.R. Reducing the risk of coronary events:
evidence from the Scandinavian Simvastatin Survival Study (4S). Am. J. Cardiol.
1995, 76, 64C-68C. Streja, L., Packard, C.J., Shepherd, J., Cobbe, S., Ford, I.
WOSCOPS Group. Factors affecting low-density lipoprotein and high-density lipoprotein
cholesterol response to pravastatin in the West Of Scotland Coronary Prevention
Study (WOSCOPS). Am. J. Cardiol. 2002, 90, 731-736.
Miller, M., Mead, L.A., Kwiterovich, P.O. Jr., Pearson, T.A.
Dyslipidemias with desirable plasma total cholesterol levels and
angiographically demonstrated coronary artery disease. Am. J. Cardiol. 1990,
65, 1-5.
Ducas, J., Silversides, C., Dembinski, T.C., Chan, M.C., Tate, R.,
Dick, A., Nixon, P., Ren, S., Shen, G.X. Apolipoprotein(a) phenotypes predict
the severity of coronary artery stenosis.Clin. Invest. Med. 2002, 25, 74-82.
Deakin, S., Leviev, I., Guernier, S., James, R.W. Simvastatin modulates
expression of the PON1 gene and increases serum paraoxonase: a role for sterol
regulatory element-binding protein-2. Arterioscler. Thromb. Vasc. Biol. 2003,
23, 2083-2089.
Hokanson, J.E. Hypertriglyceridemia and risk of coronary heart disease.
Curr. Cardiol. Rep. 2002, 4, 488-493.
Plehn, J.F., Davis, B.R., Sacks, F.M., Rouleau, J.L., Pfeffer, M.A.,
Bernstein, V., Cuddy, T.E., Moye, L.A., Piller, L.B., Rutherford, J., Simpson,
L.M., Braunwald, E. Reduction of stroke incidence after myocardial infarction
with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care
Investigators. Circulation. 1999, 99, 216-223.
Gotto, A.M. Jr. High-density lipoprotein cholesterol and triglycerides
as therapeutic targets for preventing and treating coronary artery disease. Am.
Heart J. 2002, 144, S33-S42.
Moghadasian, M.H. A safety look at currently available statins. Expert.
Opin. Drug Saf. 2002, 1, 269-274.
Bolego, C., Baetta, R., Bellosta, S., Corsini, A., Paoletti, R. Safety
considerations for statins. Curr. Opin. Lipidol. 2002, 13, 637-644.
[Back to top] Statins and Thrombin
J.W. Fenton II,
D.V. Brezniak, F.A. Ofosu, G.X. Shen, J.R. Jacobson, J.G.N.Garcia
L-Mevalonic acid is the distant precursor of cholesterol, in contrast
to cholesterol, L-mevalonic acid, its distant precursor gives rise to farnesyl
and geranylgeranyl pyrophosphates in relatively few metabolic steps. These
isoprenyl pyrophophates covalently conjugate with specific G-proteins and serve
as membrane anchors enabling them to carry out their function. Although
farnesyl-proteins may participate in signal transduction,
geranylgeranyl-proteins (e.g., Rho GTP binding proteins) are well known
to downregulate signaling pathways by inhibiting L-mevalonic acid
synthesis. Such inhibitors include 3-hydroxy-3-methylglutaryl CoA reductase
inhibitors, drugs (statins) and isoprenoids of dietary origins, where Rho
protein activation appears to be necessary for cellular-mediated thrombin
generation. Thrombin and other proteases (e.g., coagulation factor Xa,
tryptase) upregulate protease-activated receptor (PAR) synthesis and PAR
activation promotes synthesis and expression of other proteins [e.g.,
tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1)]. With the
PAR-1 activating peptide SSFLRNP, we found that either cerivastatin or atorvastatin
mitigated platelet stimulation in a time- and dose-dependent manner, as
predicted if a statin-mediated Rho pathway is required. We also found that
simvastatin decreased prothrombin fragments F1+2 in plasma from type 2
diabetics, demonstrating that statins downregulate thrombin generation. Thus,
independent of cholesterol, statins and dietary isoprenoids behave as
inhibitors of TF-dependent thrombin generation. Because thrombin has multiple
physiological functions, the 20 pleiotropic effects reported for statins may
reflect a common mechanism for downregulation of thrombin-mediated events, in
particular at the cellular level.
[Back to top] Mechanisms for Antiplatelet
Action of Statins
Luca Puccetti, Anna
Laura Pasqui, Alberto Auteri and Fulvio Bruni
Hydroxymethyl-glutaryl coenzyme A reductase inhibitors (statins) offer
important benefits for the large populations of individuals at high risk for
coronary heart and cerebrovascular disease. the overall clinical benefits
observed with statin therapy appear to be greater than what might be expected
from changes in lipid profile alone, suggesting that the beneficial effects of
such drugs may extend beyond their effects on serum cholesterol. Platelet hyperactivity
is a key step in atherothrombosis and experimental data suggest that statins
could exert an antiplatelet effect which could be involved in their protective
action. In the present review we report of the major studies in humans showing
the effect of statins on platelets, especially by the more sensitive methods to
explore platelet function such as cytofluorymetric detection of specific
proteins. Moreover we describe the putative mechanisms involved in platelet
deactivation with particular regard to the effects related to cholesterol
reduction or beyond lipid-lowering. Indeed, data from several studies suggest
some differences among compounds in terms of timing of action by modulation of
several activating pathways which could take part either in the early,
cholesterol-lowering independent, effects in the acute phase of vascular
disease or during chronic treatment.
[Back to top] Cholesterol-independent
Effects of Statins in Inflammation, Immunomodulation and Atherosclerosis
Claire Arnaud,
Niels R. Veillard and Francois Mach
Atherosclerosis and its complications still represent the major cause
of death in developed countries. Statins have revolutionized the treatment of
dyslipidemia and demonstrated their ability to reduce and prevent coronary
morbidity and mortality. Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A
(HMG-CoA) reductase, an enzyme crucial to cholesterol synthesis. The
effectiveness and rapidity of statin-induced decreases in coronary events led
to the speculation that statins possess cholesterol-independent effects. Since
mevalonate produced by the HMG-CoA reductase is not only the precursor of
cholesterol, but also of non steroidal isoprenoid compounds, such as the
farnesyl pyrophosphate and the geranylgeranyl pyrophosphate, statins also
regulate the small signaling proteins, Ras and Rho. Thus, inhibition of these
prenylated proteins might account for the non-lipid lowering effects of
statins. In this review, we describe the numerous beneficial pleiotropic
effects of statins that could modulate atherogenesis.
[Back to top] Statin-induced Vascular Smooth Muscle Cell
Apoptosis: A Possible Role in the Prevention of Restenosis?
Wolfgang Erl
Growing evidence suggests that statins are more than simple
lipid-lowering drugs. The so called pleiotropic effects of statins include
multiple actions on cells of the vasculature. A large number of studies have
confirmed that these compounds exert beneficial effects by mechanisms unrelated
to cholesterol metabolism. For example, statins have been shown to inhibit the
migration and proliferation of vascular smooth muscle cells (VSMC), and to
induce apoptosis in this cell type. It is not yet clear if the induction of
apoptosis in VSMC by statins is beneficial or detrimental. In the context of
post-angioplasty restenosis, recurrent plaque growth after intervention, the
inhibition of neointimal proliferation as well as a reduction of neointimal
cell numbers by apoptosis is appealing. Multiple animal studies and clinical
trials have therefore been undertaken to investigate effects of statin
treatment on the development of restenosis, with very controversial results.
Conversely, in advanced atherosclerotic lesions VSMC in the intima may
stabilize the plaque and prevent plaque rupture by synthesizing collagen. VSMC
in media adjacent to plaque areas or restenotic lesions should not be exposed
to apoptosis promoting agents. In this context, recent evidence suggests that
pravastatin protects such lesions by inhibiting inflammation and macrophage
activation Our recent findings together with observations from other groups
suggest that neointima cells are more sensitive to the induction of apoptosis
than media VSMC. Importantly, statins were found to preferentially induce
apoptosis in neointimal VSMC in our study. The purpose of the present review is
to summarize statin effects on proliferation and apoptosis in VSMC in vitro
and in vivo. Furthermore, the development of drug-coated stents may help
to deliver high local doses of statins to enhance their effectiveness in the
treatment of post-angioplasty restenosis.
[Back to top] Three’s Company: Regulation of Cell Fate by Statins
Joannis E. Vamvakopoulos
Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (statins), the
rate-limiting enzyme of the mevalonate biosynthetic pathway, are currently the
leading prescription drugs worldwide. Programmed cell death (apoptosis) is a
powerful physiological regulator of cellular development, function and
dynamics. Statins are known to induce cellular apoptosis in vitro;
however, the clinical relevance of this action remains controversial. This
paper draws from 15 years’ worth of research to explore the impact of statin
treatment on cell fate, as represented by the interlinked processes of cellular
growth, differentiation and apoptosis. In particular, I outline our current
understanding of the pertinent molecular mechanisms; and discuss the evidence
for clinical relevance of statin-induced apoptosis.
[Back to top] The Role of Statins in
Oxidative Stress and Cardiovascular Disease
Dominic S. Ng
Statins have emerged as a highly efficacious class of drugs in the
prevention of cardiovascular events. The primary mechanism of its
cardioprotective effect is likely through its effectiveness in lowering serum
lipids, particularly the low density lipoprotein (LDL) fractions. Recent
studies suggest that statins also confer direct beneficial effects on the
vascular cells in the attenuation of the atherogenic process through a variety
of mechanisms. It remains the current dogma that oxidative modification of the
LDL particles in the vessel wall plays a critical role for these lipoprotein
particles to intiate the atherogenic cascade. The current failure of a number
of antioxidants, which includes vitamin E, to favorably impact on the
cardiovascular outcome in large scale clinical trials attests to the complexity
of the oxidation processes in biological systems. In this review, we will
highlight the current advances in a number of endogenous pro-oxidative and
anti-oxidative systems in how they contribute to the net oxidative stress and
how statin drugs may modulate this complex array of pro- and anti-oxidative
processes.
[Back to top] Biological Properties of Baicalein in Cardiovascular System
Yu Huang, Suk-Ying Tsang, Xiaoqiang Yao and Zhen-Yu Chen
The dried roots of Scutellaria baicalensis (S.
baicalensis) Georgi (common name: Huangqin in China) have been widely
employed for many centuries in traditional Chinese herbal medicine as popular
antibacterial and antiviral agents. They are effective against staphylococci,
cholera, dysentery, pneumococci and influenza virus. Baicalein, one of the
major flavonoids contained in the dried roots, possesses a multitude of
pharmacological activities. The glycoside of baicalein, baicalin is a potent
anti-inflammatory and anti-tumor agent. This review describes the biological
properties of baicalein (Table 1), which are associated with the prevention and
treatment of cardiovascular diseases. Baicalein is a potent free radical
scavenger and xanthine oxidase inhibitor, thus improving endothelial function
and conferring cardiovascular protective actions against oxidative
stress-induced cell injury. Baicalein lowers blood pressure in renin-dependent
hypertension and the in vivo hypotensive effect may be partly attributed
to its inhibition of lipoxygenase, resulting in reduced biosynthesis and
release of arachidonic acid-derived vasoconstrictor products. On the other
hand, baicalein enhances vasoconstricting sensitivity to receptor-dependent
agonists such as noradrenaline, phenylephrine, serotonin, U46619 and
vasopressin in isolated rat arteries. The in vitro effect is likely
caused by inhibition of an endothelial nitric oxide-dependent mechanism. The
anti-thrombotic, anti-proliferative and anti-mitogenic effects of the roots of S.
baicalensis and baicalein are also reported. Baicalein inhibits
thrombin-induced production of plasminogen activator inhibitor-1, and
interleukin-1ß- and tumor necrosis factor-a-induced adhesion molecule expression in
cultured human umbilical vein endothelial cells. The pharmacological findings
have highlighted the therapeutic potentials of using plant-derived baicalein
and its analogs for the treatment of arteriosclerosis and hypertension.
[Back to top] Common Therapeutic Strategies in the Management of Sexual
Dysfunction and Cardiovascular Disease
T.M. Hale, J.L. Hannan, J.P.W. Heaton, and M.A. Adams
Sexual dysfunction is a frequent complication of treated and untreated
cardiovascular disease. In fact, ~30% of hypertensives have been found to
suffer from erectile dysfunction (ED) resulting from arterial dysfunction.
Recent evidence has suggested that ED may be an early indicator of subclinical
cardiovascular disease. In women, the evidence is similar, but more limited,
showing that in hypertensive patients there is an increased prevalence of
sexual dysfunction involving decreased vaginal lubrication, decreased orgasm,
and increased pain. Clouding the issue, however, is that some antihypertensive
agents may induce sexual dysfunction in hypertensives with normal sexual function.
In contrast to the chronic treatments used in hypertension, therapies for ED
involve acute treatments (none currently approved for women) targeting
vasodilation of penile arteries, resulting in erection. Common to the treatment
of hypertension and ED is that the current therapies were not designed to
target underlying disorders of local, neural, vascular, or endocrine origin. In
fact, while blood pressure is lowered, and erectile responses are improved with
the respective therapies, the causal abnormalities may progress thereby
limiting the long-term effectiveness of the medication. Some antihypertensive
agents have been shown to have additional effects beyond blood pressure
reduction and their impact on sexual function is a key focus of this review. This
review examines the current and future strategies for treatments of male and
female sexual dysfunction and the potential for therapeutic modalities that go
beyond the recovery of the responses by targeting the fundamental mechanisms
common to both sexual dysfunction and cardiovascular disease.