Current
Pharmaceutical Biotechnology
ISSN: 1389-2010
Current Pharmaceutical Biotechnology
Volume 7, Number 2, April 2006
Contents
Oxidative Stress and Cardiovascular System
Guest Editor: Kenichi Yasunari
Editorial Pp. 67
What We Learnt from Randomized Clinical Trials
and Cohort Studies of Antioxidant Vitamins? : Focus on Vitamin
E and Cardiovascular Disease Pp. 69-72
S. Ueda and K. Yasunari
[Abstract]
Reactive Oxygen Species Formation by Polymorphonuclear
Cells and Mononuclear Cells as a Risk Factor of Cardiovascular
Diseases Pp. 73-80
K. Yasunari, T. Watanabe and M. Nakamura
[Abstract]
Current Understanding of the Mechanism and Role
of ROS in Angiotensin II Signal Transduction Pp.
81-86
H. Suzuki, G.D. Frank, H. Utsunomiya, S. Higuchi
and Satoru Eguchi
[Abstract]
New Biotechological Methods to Reduce Oxidative
Stress in the Cardiovascular System: Focusing on the Bach1/Heme
Oxygenase-1 Pathway Pp. 87-93
R. Ozono
[Abstract]
Anti-Oxidant Gene Therapy by NFκB
Decoy Oligodeoxynucleotide Pp. 95-100
H. Nakagami, N. Tomita, Y. Kaneda, Y. Kaneda, T. Ogihara
and R. Morishita
[Abstract]
Oxidative Stress on Progenitor and Stem Cells in
Cardiovascular Diseases Pp. 101-108
E.-H. Yao, Y. Yu and N. Fukuda
[Abstract]
Oxidative Stress, Endothelial Function and Angiogenesis
Induced by Cell Therapy and Gene Therapy Pp. 109-116
Y. Higashi, K. Nishioka, T. Umemura, K. Chayama
and M. Yoshizumi
[Abstract]
General Articles
Chronic Obstructive Pulmonary Disease and Oxidative
Stress Pp. 117-123
W. Domej, Z. Földes-Papp, E. Flögel and B. Haditsch
[Abstract]
The Role of Insulin-Like Growth Factor I Components
in the Regulation of Vitamin D Pp. 125-132
J. Manuel Gómez
[Abstract]
Abstracts
[Back to top]
Editorial
Reactive oxygen species (ROS) are produced by many
cell types of cardiovascular system. In healthy subjects,
intrinsic antioxidative substances including alpha-tocopherol
(vitamin E) and vitamin C reduces ROS and protect cardiovascular
cells from injury. However, excessive production of ROS and/or
decreased antioxidative activity in cardiovascular cells induces
oxidative stress and causes endothelial dysfunction and a
variety of cardiovascular diseases, which is one of the main
topic of cardiovascular medicine.
In this issue, review by top researchers are organized as
follows:
a). What is the present and real questions to be solved for
reducing cardiovascular diseases caused by oxidative stress
from the viewpoints of cardiologists? Professor Ueda summarizes
the applications of vitamin E antioxidative properties.
b). For the evaluation of oxidative stress in cardiovascular
cells, experimental animals and whole human body by the biochemical
and biotechnological methods, Dr. Yasunari exemplifies the
measurement of oxidative stress of leukocytes by fluorescence
compounds and flow cytometry.
c). Modification of oxidative stress by the natural and pharmaceutical
compounds in cellular and whole body. Drs. Suzuki and Eguchi
review the role of angiotensin II on oxidative stress in cardiovascular
system. Dr. Ozono describes new biotechological methods to
reduce oxidative stress in the cardiovascular system, focusing
on the Bach1/heme oxygenase-1 pathway.
d). New biotechnological methods to reduce oxidative stress
in cardiovascular medicine include bone marrow cell transplantation
and gene therapy. Dr. Nakagami presents a gene therapy approach
using by NF-κB
decoy oligonucleotides. Dr. Yao and Fukuda review the oxidative
stress on progenitor and stem cells in cardiovascular diseases
and Dr. Higashi in bone bone marrow cell transplantation.
This special issue should provide the reader with a better
understanding of some of the clinical applications of pharmaceutical
biotechnology and should also help researchers in the field
of biotechnological pharmacology.
Kenichi Yasunari MD, PhD, FAHA
Guest Editor
Department of Medicine and Cardiology
Osaka City University Graduate School of Medicine
Japan
Tel: 81-6-6645-3803
Fax: 81-6-6646-6808
E-mail: yasunari@osaka.med.or.jp
[Back to top]
What We Learnt from Randomized Clinical
Trials and Cohort Studies of Antioxidant Vitamins? : Focus
on Vitamin E and Cardiovascular Disease
S. Ueda and K. Yasunari
There is no doubt that oxidative stress is pivotally involved
in the process of atherosclerosis. Thus antioxidants, particularly
vitamin E, have been expected to retard the development of
atherosclerosis. In fact, several cohort studies suggested
reduced cardiovascular risk in persons taking vitamin E supplements.
However, randomized clinical trials of vitamin E did not show
any benefit of vitamin E supplementation in terms of prevention
of coronary heart disease and death. Discrepancy between cohort
studies and randomized clinical trials may be partly explained
by difference in coronary risk in study participant. However,
use of vitamin E supplementation in low risk population has
not been justified yet.
[Back to top]
Reactive Oxygen Species Formation by Polymorphonuclear
Cells and Mononuclear Cells as a Risk Factor of Cardiovascular
Diseases
K. Yasunari, T. Watanabe and M. Nakamura
To better identify patients at high risk for cardiovascular
events, several markers of risk have been proposed for use
in screening. Recently, oxidative stress and inflammation
have been evaluated as potential tools for prediction of the
risk of cardiovascular events. Among them, we have measured
reactive oxygen species (ROS) formation by polymorphonuclear
cells (PMNs) and mononuclear cells (MNCs), since they may
be a possible link between inflammation and oxidative stress.
ROS formation by PMNs and MNCs was measured by a gated flow
cytometric assay. Such biotechnological method of measuring
ROS formation by PMNs and MNCs will make it possible that
we measure vascular oxidative stress and vascular inflammation
at the same time from only small amount of blood.
We will state in this review that ROS formation by PMNs and
MNCs are regulated by different mechanisms, although PMNs
and MNCs are circulating in the same blood. Moreover, we will
state that ROS formation by PMNs are regulated by blood pressure,
Hb A1C
and oxidided LDL. ROS formation by MNCs are regulated by vascular
inflammation, and that ROS formation by MNCs are also related
to various cardiovascular risks such as LV mass, norepinephrine,
IMT, and nocturnal blood pressure.
[Back to top]
Current Understanding of the Mechanism and Role of
ROS in Angiotensin II Signal Transduction
H. Suzuki, G.D. Frank, H. Utsunomiya, S. Higuchi
and Satoru Eguchi
Reactive oxygen species (ROS) are proposed to induce cardiovascular
diseases, such as atherosclerosis and hypertension, through
several mechanisms. One such mechanism involves ROS acting
as intracellular second messengers, which lead to induction
of unique signal transductions. Angiotensin II (AngII), a
potent cardiovascular pathogen, stimulates ROS production
through vascular NADPH oxidases. The ROS production induced
by AngII activates downstream ROS-sensitive kinases that are
critical in mediating cardiovascular remodeling. Recent advances
in gene transfer/knockout techniques have lead to numerous
in vitro and in vivo studies that identify the
potential components and mechanisms of ROS signal transduction
by AngII which promote cardiovascular remodeling. In this
review, we will focus our discussion on the signal transduction
research elucidating ROS production and function induced by
AngII using currently available molecular biotechnologies.
[Back to top]
New Biotechological Methods to Reduce Oxidative Stress
in the Cardiovascular System: Focusing on the Bach1/Heme Oxygenase-1
Pathway
R. Ozono
Oxidative stress is involved in the mechanism of atherosclerotic
lesion formation and in the mechanisms underlying the development
of other pathogenic conditions of the cardiovascular system,
including endothelial dysfunction, hypertension, and heart
failure. Reducing oxidative stress may be a reasonable therapeutic
approach to treat cardiovascular diseases. HO-1 is a cytoprotective
enzyme that is induced in response to oxidative stress and
degrades heme into carbon monoxide (CO) and bilirubin, both
of which have cytoprotective effects. A substantial body of
evidence suggests that introduction of HO-1, either pharmacologically
or by a gene delivery technique, confers cytoprotection in
ischemic heart disease and atherosclerosis in animals. Recent
studies have revealed that CO has anti-inflammatory properties
and that administration of CO provides protection against
atherosclerosis and ischemic heart disease. Discovery of Bach1,
a transcriptional repressor of HO-1, has greatly contributed
to the understanding of the regulation of HO-1 expression,
providing a clue to a development of alternative method to
enhance HO activity. Bach1 normally represses HO-1 expression.
However, upon exposure to oxidative stress, Bach1 loses its
repressive activity and is exported out of the nucleus, which
in turn results in the upregulation of HO-1. Bach1 knockout
mice, expressing an increased amount of HO-1, are resistant
to pro-atherosclerotic and ischemic stresses. These findings
indicate that inhibition of Bach1 may be a novel approach
to enhance protection against stress. In summary, the Bach1-HO-1
system is an important defense mechanism against oxidative
stress. Development of a safe and effective method to enhance
this pathway, such as Bach1 inhibitor, may be of great clinical
relevance.
[Back to top]
Anti-Oxidant Gene Therapy by NFκB
Decoy Oligodeoxynucleotide
H. Nakagami, N. Tomita, Y. Kaneda, Y. Kaneda, T. Ogihara
and R. Morishita
Oxidative stress to cardiovascular cells induced by an interaction
of multiple cytokines and adhesion molecules has been postulated
to be responsible for cardiovascular disease. Since nuclear
factor-κB
(NFκB)
also plays a pivotal role in the coordinated transactivation
of cytokine and adhesion molecule genes, we utilized oligodeoxynucleotides
(ODNs) as “decoy” cis-elements that block the
binding of nuclear factors to promoter regions of targeted
genes, resulting in the inhibition of gene transactivation.
Indeed, transfection of NFκB
decoy ODNs into coronary artery effectively prevented trans-activation
of essential cytokine and adhesion molecule protein expression,
and thereby protected the myocardium from infarction. Transfection
of NFκB
decoy ODNs into balloon-injured carotid artery or porcine
coronary artery markedly reduced neointimal formation. Thus,
a clinical trial using NFκB
decoy ODNs to treat restenosis was started in 2002. Recently,
the therapeutic target utilizing NFκB
decoy has been expanded to glomerulonephritis, rheumatoid
arthritis, atopic dermatitis and osteoporosis. Moreover, the
clinical trials to treat RA patients were initiated in 2003
and a Phase I/IIa human clinical trial using NFκB
decoy ODNs to treat atopic dermatitis was initiated in December
2001. Topical application of NFκB
decoy ODNs exhibited marked therapeutic effects on the facial
skin condition of patients with atopic dermatitis. The covalently
modified ODNs were developed by enzymatically ligating two
identical molecules, thereby preventing their degradation
by exonucleases. Indeed, the modified decoy ODNs possess increased
nuclease resistance and are transported more efficiently into
cells. Although there are still unresolved issues, decoy ODN
drugs should become a reality.
[Back to top]
Oxidative Stress on Progenitor and Stem Cells in Cardiovascular
Diseases
E.-H. Yao, Y. Yu and N. Fukuda
There is accumulating evidence that reactive oxygen species
(ROS) play major roles in the initiation and progression of
cardiovascular dysfunction associated with diseases such as
hyperlipidemia, diabetes mellitus, hypertension, ischemic
heart disease, and chronic heart failure. ROS produced by
migrating inflammatory cells as well as vascular cells (endothelial
cells, vascular smooth muscle cells, and adventitial fibroblasts)
have distinct functional effects on each cell type. These
effects include cell growth, apoptosis, migration, inflammatory
gene expression and matrix regulation. ROS, through regulating
vascular cell function, can play a central role in normal
vascular physiology, and contribute substantially to the development
of cardiovascular diseases. Excessive production of ROS is
an essential mechanism underlying the pathogenesis of endothelial
dysfunction and cardiovascular disease. Stem cells hold great
promise for tissue repair and regenerative medicine, and endothelial
progenitor cells (EPC) play a significant role in neovascularization
of ischemic
tissue. Recent studies have shown that cardiovascular risk
factors such as hypertension, hypercholesterolemia, diabetes
and cigarette smoking are inversely correlated with EPC number
and function. Understanding the mechanisms, that regulate
EPC function may provide new insights into the pathogenesis
of vasculogenesis and may promote development of specific
therapies to prevent ROS production and ultimately correct
EPC dysfunction. We have demonstrated the angiotensin II receptor
blockers improve EPC dysfunction through antioxidative mechanisms.
In the present review, we describe our current understanding
of the contributions of oxidative stress to progenitor and
stem cell dysfunction in cardiovascular disease and focus
on the potential mechanisms that underlie oxidative stress-induced
damage of progenitor and stem cells.
[Back to top]
Oxidative Stress, Endothelial Function and Angiogenesis
Induced by Cell Therapy and Gene Therapy
Y. Higashi, K. Nishioka, T. Umemura, K. Chayama
and M. Yoshizumi
Recently, clinical studies have shown that novel therapies,
including cell implantation and transfer of gene encoding
for angiogenic growth factors, are effective in patients with
critical limb ischemia who have no other treatment option.
This concept is called therapeutic angiogenesis. Cell therapy
involves implantation of bone-marrow or peripheral mononuclear
cells and endothelial progenitor cells (CD34+
cells) in the gastrocnemius of the ischemic leg. Gene therapy
involves delivery of vascular endothelial growth factor and
fibroblast growth factor using a plasmid or adenoviral vector.
Critical limb ischemia is associated with endothelial dysfunction
as well as excess oxidative stress. A balance of oxidative
stress and nitric oxide play an important role in the development
of atherosclerosis in patients with peripheral arterial diseases.
It has been reported that both cell therapy and gene therapy
improve endothelial function in the resistant artery of an
ischemic limb. Cell therapy or gene therapy in combination
with pharmacological therapy as an antioxidant could be useful
for restoration of endothelial function and prevention of
development of atherosclerosis in patients with critical limb
ischemia. In this review, we discuss the relationships between
oxidative stress, endothelial function, and angiogenesis and
the mechanism by which therapeutic angiogenesis improves endothelial
function.
[Back to top]
Chronic Obstructive Pulmonary Disease and Oxidative
Stress
W. Domej, Z. Földes-Papp, E. Flögel and B. Haditsch
The respiratory tract as the main entrance for various
inhalative substances has great potential to generate reactive
species directly or indirectly in excess. Thus, heavy smokers
are at high risk for development, impairment and failed response
to treatment of chronic obstructive pulmonary disease (COPD).
The article is an update regarding the influence of reactive
oxygen (ROS) and nitrogen (RNS) species on COPD; however,
we do not intend to describe ROS and RNS actions on the entire
lung tissue. Here, we focus on the airways, because in human
most of the described effects of ROS and RNS species are measured
on respiratory epithelial cells obtained by bronchoscopy.
ROS and RNS species are physiological compounds in cells and
risk factors for several respiratory diseases. In general,
both kinds of species are thermo-dynamically stabile, but
their reaction behaviors in cellular environments are very
different. For example, the life times of the superoxide anion
radical range from micro/milliseconds up to minutes and even
hours in in-vitro model systems. Oxidative stress
by cigarette smoke was investigated in detail by the authors
of this article. In addition, original studies by the authors
on the amount of fine particulate matter and trace elements
in lung biopsies after defined inhalation indicate a distortion
of the equilibrium between oxidants and antioxidants. We also
try to present some modern views with respect to genomic medicine
for future therapeutic perspectives, although this is an upcoming
sector of COPD therapy.
[Back to top]
The Role of Insulin-Like Growth Factor I Components
in the Regulation of Vitamin D
J. Manuel Gómez
Several factors are known to be involved in the regulation
of vitamin D and sunlight and diet are the two sources in
humans, but the relative importance of each of them is not
well defined. Vitamin D, parathyroid hormone and serum insulin-like
growth factor-I (IGF-I) were found to be independent predictors
of total bone density. Thus, the growth hormone (GH)/IGF-I
is thought to play an important role in the regulation of
bone mineral density and the skeleton is second only to the
liver as a source of circulating levels of IGF-I. The mechanisms
by which IGF-I may influence bone metabolism is not fully
understood but they are a predictor of bone mass density and
are positively associated with vitamin D concentrations. There
is a physiological decline of the GH/IGF axis with ageing.
The high affinity IGF-binding proteins (IGFBP-1 to 6) have
also been involved in IGF-I regulation, and it is important
to include the IGF-independent properties, particularly those
of IGFBP3 that may be involved in the osteoblastic differentiation
observed in human bone marrow stromal cell cultures. These
hormones have been shown to up regulate each other. 1,25-(OH)
D3
has been shown to promote the action of IGF-I by increasing
IGF-I receptors and IGF-I can also elevate 1,25-(OH) D3
concentrations by stimulating the hydroxylation of 25-(OH)
D3
in the active 1,25-(OH) D3
hormone. Both GH and IGF-I significantly increased renal 1α-hydroxylase
expression and serum 1, 25-(OH) D3
concentrations.
In prostate cells, 1,25-(OH) D3
is growth inhibitory for many established cell lines and the
role of IGFBPs, especially IGFBP-3, can be growth inhibitory
or stimulatory and IGFBP-3 expression increases in response
to 1,25-(OH) D3,
or its analogs, in established prostate cancer cell lines.
Body fat is inversely associated with 25-(OH) D3
in relation to with anthropometric measures, indicating a
specific role of adipose tissue.
IGF-I may be involved in both normal and abnormal fetal growth
and stimulation of IGF-I synthesis during normal pregnancy
may be associated with an increase in GH production by the
placenta. Thus, maternal and umbilical cord serum IGF-I and
1,25-(OH) D3
concentrations are lower in preeclampsia and umbilical cord
serum IGF-I, IGFBP-1 and IGFBP-3 concentrations are associated
with low newborn birth weights.
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