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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 15, Number 24, 2009
Contents
Therapeutic Angiogenesis and Regeneration
in Cardiovascular Diseases
Executive Editor: Masafumi Takahashi
Editorial: Pp. 2759
Role of Vascular Progenitor Cells in Cardiovascular
Disease Pp. 2760-2768
K. Tanaka and M. Sata
[Abstract] [Purchase
Article]
Therapeutic Angiogenesis for Peripheral
Artery Diseases by Autologous Bone Marrow Cell Transplantation
Pp. 2769-2777
S. Matoba and H. Matsubara
[Abstract] [Purchase
Article]
Therapeutic Neovascularization by the
Implantation of Autologous Mononuclear Cells in Patients with
Connective Tissue Diseases Pp. 2778-2783
M. Takahashi, A. Izawa, Y. Ishigatsubo,
K. Fujimoto, M. Miyamoto, T. Horie, Y. Aizawa, J. Amano, S.
Minota, T. Murohara, H. Matsubara and U. Ikeda
[Abstract] [Purchase
Article]
Autologous Adipose-Derived Regenerative
Cells for Therapeutic Angiogenesis Pp. 2784-2790
T. Murohara, S. Shintani and K.
Kondo
[Abstract] [Purchase
Article]
Cardiac Applications for Human Pluripotent
Stem Cells Pp. 2791-2806
Y. Shiba, K.D. Hauch and M.A. Laflamme
[Abstract] [Purchase
Article]
Cell Sheet-Based Myocardial Tissue Engineering:
New Hope for Damaged Heart Rescue Pp. 2807-2814
T. Shimizu, H. Sekine, M. Yamato and
T. Okano
[Abstract] [Purchase
Article]
General Articles
Are the Pleiotropic Effects of Telmisartan
Clinically Relevant? Pp. 2815-2832
C.V. Rizos, M.S. Elisaf and E.N.
Liberopoulos
[Abstract] [Purchase
Article]
Function and Frustration of Multi-Drug
ABC Exporter Protein and Design of Model Proteins for Drug
Delivery Using Protein Hydration Thermodynamics Pp.
2833-2867
D.W. Urry, K.D. Urry, W. Szaflarski, M.
Nowicki and M. Zabel
[Abstract] [Full
Text Article]
Abstracts
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Editorial: Therapeutic Angiogenesis and Regeneration
in Cardiovascular Diseases
Ischemic cardiovascular diseases, such as coronary
artery disease and peripheral arterial disease, are significant
medical problems worldwide and, in particular, coronary artery
disease remains a major cause of morbidity and mortality in
the Western world. Despite significant progress in revascularization
procedures, a substantial number of patients with ischemic
cardiovascular diseases are either not candidates for these
procedures or can be only partially revascularized. Nearly
a decade ago, Asahara et al. [1] identified endothelial
progenitor cells (EPCs) from circulating adult peripheral
mononuclear cells. Since then, accumulating evidence indicates
that bone marrow- and peripheral blood-derived progenitor/stem
cells have therapeutic potential for the treatment of patients
with cardiovascular diseases such as peripheral arterial diseases
and myocardial ischemia. Furthermore, therapeutic application
of human pluripotent stem cells such as embryonic stem (ES)
and pluripotent stem (iPS) cells for cardiovascular diseases
has been investigated recently. The aim of this issue is to
provide a review of the basic and clinical advances in therapeutic
angiogenesis and regeneration in cardiovascular diseases.
In the current issue of Current Pharmaceutical Design, therapeutic
angiogenesis and regeneration by progenitor/stem cells are
carefully reviewed by the experts who have contributed in
this field of research. In the first article by Tanaka and
Sata [2], recent findings on the role of vascular progenitor
cells, such as EPCs and smooth muscle cell progenitor cells
(SMPCs), in cardiovascular disease are overviewed. Matoba
and Matsubara [3], who previously conducted TACT study, reported
the efficacy and long-term outcome of therapeutic neovascularization
by autologous bone marrow cells implantation for PAD patients.
In addition, we discussed the abnormalities of EPCs in patients
with connective tissue diseases (CTDs) such as systemic scleroderma
(SSc) and systemic lupus erythematosus (SLE), and reported
clinical pilot study of autologous cell therapy for critical
digit ischemia in patients with CTDs [4]. Murohara et
al. [5] reviewed adipose-derived regenerative cells for
therapeutic angiogenesis. Shiba et al. [6] discussed
the phenotype of human ES and iPS cell-derived cardiomyocytes,
the state of preclinical transplantation studies, and potential
approaches to overcoming the aforementioned hurdles to clinical
application using these stem cells. In the final article by
Shimizu et al. [7], cell sheet-based myocardial tissue
engineering was reviewed. I wish to thank all the authors
for their essential contribution and believe that this issue
may be useful for readers working in basic and translational
medical science and for clinicians to update information on
the trends in the filed of cardiovascular diseases.
References
[1] Asahara T, Murohara T, Sullivan A, Silver M, van der Zee
R, Li T, et al. Isolation of putative progenitor
endothelial cells for angiogenesis. Science 1997; 275: 964-7.
[2] Tanaka K, Sata M. Role of vascular progenitor cells in
cardiovascular disease. Curr Pharm Des 2009; 15(24): 2760-2768.
[3] Matoba S, Matsubara H. Therapeutic angiogenesis for peripheral
artery diseases by autologous bone marrow cell transplantation.
Curr Pharm Des 2009; 15(24): 2769-2777.
[4] Takahashi M, Izawa A, Ishigatsubo Y, Fujimoto K, Miyamoto
M, Horie T, Aizawa Y, Amano J, Minota S, Murohara T, Matsubara
H, Ikeda U. Therapeutic neovascularization by implantation
of autologous mononuclear cells for patients with connective
tissue diseases. Curr Pharm Des 2009; 15(24): 2778-2783.
[5] Murohara T, Shintani S, Kondo K. Autologous adipose-derived
regeneration cells for therapeutic angiogenesis. Curr Pharm
Des 2009; 15(24): 2784-2790.
[6] Shiba Y, Hauch KD, Laflamme MA. Cardiac application for
human pluripotent stem cells. Curr Pharm Des 2009; 15(24):
2791-2806.
[7] Shimizu T, Sekine H, Yamato M, Okano T. Cell sheet-based
myocardial tissue engineering: New hope for damaged heart
rescue. Curr Pharm Des 2009; 15(24): 2807-2814.
Masafumi Takahashi, MD, PhD
Department of Cardiovascular Medicine
Shinshu University Graduate School of Medicine
Matsumoto
and
Center for Molecular Medicine
Jichi Medical University, Tochigi
Japan
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Role of Vascular Progenitor Cells in Cardiovascular
Disease
K. Tanaka and M. Sata
It is a widely accepted view that vascular repair results
from migration and proliferation of adjacent vascular cells.
On the other hand, accumulating evidence suggests that bone
marrow cells can give rise to endothelial-like cells and smooth
muscle-like cells that potentially contribute to vascular
healing, remodeling and lesion formation under physiological
and pathological conditions. However, some recent reports
indicated controversial results and cast a doubt on the specificity
of the method to detect differentiation of ectopic cells.
Here, we overview recent findings on the role of vascular
progenitor cells in cardiovascular diseases and provide possible
explanation why different conclusions have been drawn from
different animal experiments.
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Article]
Therapeutic Angiogenesis for Peripheral Artery Diseases by
Autologous Bone Marrow Cell Transplantation
S. Matoba and H. Matsubara
Critical limb ischemia (CLI) is a terminal stage of peripheral
artery disease (PAD). The number of patients with CLI is increasing,
and the disease has a major impact on patients’ quality
of life. In spite of the marked advances in surgery and interventional
angioplasty, a large number of patients require revascularization.
To treat these patients, cell based angiogenesis is attracting
a great deal of attention as a new strategy.
“Therapeutic angiogenesis” is a term that has
become widely used in the last decade. Despite negative results
in several clinical trials of cytokine-based angiogenesis,
cell based therapy produced effective angiogenesis. This cell-based
angiogenesis originates from persistent basic research. The
first clinical randomized pilot study was reported in 2002.
Up to now, more than 30 clinical studies on the use of mononuclear
cells or progenitor cells for the treatment have been published.
As the prognosis of the patients with CLI is poor, it has
been discussed with respect to their safety and feasibility.
With the increasing number of treated patients, the accumulated
outcomes from these clinical studies are demonstrating this
therapy to be reliable. They reveal indications of the stage
of the patients with PAD and the timing of treatments. However,
clinical data concerning long time prognosis and a standardized
protocol have not been discussed sufficiently.
This review summarises data from recent clinical outcomes
from 17 studies (11 involving BMMNC that included >10
patients, 6 involving PBMNC that included >10
patients) that are treating patients with PAD by autologous
cell transplantation.
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Article]
Therapeutic Neovascularization by the Implantation of Autologous
Mononuclear Cells in Patients with Connective Tissue Diseases
M. Takahashi, A. Izawa, Y. Ishigatsubo,
K. Fujimoto, M. Miyamoto, T. Horie, Y. Aizawa, J. Amano, S.
Minota, T. Murohara, H. Matsubara and U. Ikeda
Vasculopathy in patients with connective tissue diseases
(CTDs), including systemic sclerosis (SSc) and systemic lupus
erythematosus (SLE), is a serious complication that mainly
affects small arteries and capillaries, reduces the blood
flow and causes progressive tissue ischemia. Recently, CTD
patients have been reported to have abnormalities in circulating
endothelial progenitor cells (EPCs); these abnormalities are
believed to contribute to the pathophysiology of vasculopathy
and to the premature and accelerated development of atherosclerosis
in CTD patients. Furthermore, we are currently conducting
a clinical pilot study to determine the efficacy of implanting
autologous mononuclear cells obtained from the bone marrow
and peripheral blood into the ischemic digits or limbs of
CTD patients. In this review, we discuss the role of EPCs
in the process of neovascularization and in the pathophysiology
of CTDs, and we describe a clinical pilot study on the use
of autologous cell therapy for treating ischemic digits in
patients with CTDs.
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Article]
Autologous Adipose-Derived Regenerative Cells for Therapeutic
Angiogenesis
T. Murohara, S. Shintani and K.
Kondo
Therapeutic angiogenesis is an important means to salvage
tissues against severe ischemic diseases in patients with
no option for other vascular intervention. A number of recent
studies implicated potentials of cell-based therapeutic angiogenesis
using autologous bone marrow mononuclear cells, CD34+
cells, peripheral blood mononuclear cells, and so on. Subcutaneous
adipose tissues can be harvested by relatively easy methods.
Recent studies indicated that adipose tissues contain progenitor
cells or regenerative cells that can give rise to several
mesenchymal lineages. Moreover, these progenitor cells can
release multiple angiogenic growth factors and cytokines/chomokines
including vascular endothelial growth factor (VEGF), hypatocyte
growth factor (HGF) and chemokine stromal cell-derived factor-1
(SDF-1). The combination of these biological properties of
adipose-derived regenerative cells (ADRCs) implicates that
autologous adipose tissue will be a useful cell source for
therapeutic angiogenesis in the next generation.
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Cardiac Applications for Human Pluripotent Stem Cells
Y. Shiba, K.D. Hauch and M.A. Laflamme
Human embryonic stem cells (hESCs) and induced pluripotent
stem cells (hiPSCs) can self-renew indefinitely, while maintaining
the capacity to differentiate into useful somatic cell types,
including cardiomyocytes. As such, these stem cell types represent
an essentially inexhaustible source of committed human cardiomyocytes
of potential use in cell-based cardiac therapies, high-throughput
screening and safety testing of new drugs, and modeling human
heart development. These stem cell-derived cardiomyocytes
have an unambiguous cardiac phenotype and proliferate robustly
both in vitro and in vivo. Recent transplantation
studies in preclinical models have provided exciting proof-of-principle
for their use in infarct repair and in the formation of a
“biological pacemaker”. While these successes
give reason for cautious optimism, major challenges remain
to the successful application of hESCs (or hiPSCs) to cardiac
repair, including the need for preparations of high cardiac
purity, improved methods of delivery, and approaches to overcome
immune rejection and other causes of graft cell death. In
this review, we describe the phenotype of hESC- and hiPSC-derived
cardiomyocytes, the state of preclinical transplantation studies
with these cells, and potential approaches to overcome the
aforementioned hurdles.
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Cell Sheet-Based Myocardial Tissue Engineering: New Hope for
Damaged Heart Rescue
T. Shimizu, H. Sekine, M. Yamato and
T. Okano
Regenerative therapy has currently emerged as one of
the most promising treatments for the patients suffering from
severe heart failure. Several cell therapies by direct injection
have been already clinically performed. However, significant
cell loss due to physical strain, primary hypoxia or cell
wash-out has become problematic. To overcome this obstacle,
tissue engineered myocardial patch transplantation has been
examined as the second generation cell therapy. Furthermore
several research groups have challenged to engineer pulsatile
myocardial tissues/organs using beating cardiomyocytes. Among
several tissue engineering technologies, we have developed
cell sheet-based tissue engineering, which utilize two-dimensional
(2-D) cell sheets harvested from temperature-responsive culture
surfaces and create three-dimensional (3-D) tissues by stacking
cell sheets without generally utilized scaffolds. Several
types of cell sheet-based patches have improved damaged heart
function in rat, canine and pig models. Stacked cardiomyocyte
sheets simultaneously beat in macroscopic view both in
vitro and in vivo and revealed characteristic
structures of native heart tissue. As a possible solution
for scaling up, multi-step transplantation of triple-layer
cell sheets was performed and finally, 10-time transplantations
have realized about 1 mm-thick functional myocardial tissue.
As further advanced therapy, functional myocardial tubes have
been also engineered by wrapping cell sheets. Cell sheet-based
tissue engineering should have enormous potential in myocardial
tissue regenerative medicine and rescue many patients suffering
severe heart failure.
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Are the Pleiotropic Effects of Telmisartan Clinically Relevant?
C.V. Rizos, M.S. Elisaf and E.N.
Liberopoulos
Hypertension is one of the major risk factors for cardiovascular
disease. Angiotensin receptor blockers (ARBs) are a class
of antihypertensive drugs with established efficacy and favorable
safety profile. Telmisartan, a member of the ARB family, holds
some additional traits which differentiate it from the rest
ARBs. A pivotal role in these characteristics plays its ability
to partially activate the peroxisome proliferator activated
receptor-γ,
which in turn controls a number of metabolism-related genes.
Indeed, telmisartan has shown a number of pleiotropic effects
in experimental and clinical studies. These include the amelioration
of insulin resistance, improvement of lipid profile and favorable
fat redistribution. Moreover, telmisartan has been associated
with beneficial effects on vascular function, cardiac remodeling
and renal function. However, do all these pleiotropic effects
translate into clinical benefit? Recent studies have tried
to answer this question with promising but not definitive
results.
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[Full
Text Article]
Function and Frustration of Multi-Drug ABC Exporter Protein
and Design of Model Proteins for Drug Delivery Using Protein
Hydration Thermodynamics
D.W. Urry, K.D. Urry, W. Szaflarski, M.
Nowicki and M. Zabel
The mechanism is presented whereby simultaneous hydrolysis
of two molecules of ATP in the ATP-binding cassette (ABC)
exporter protein, Sav 1866, opens a transmembrane channel
to pump drug out of the cell and confers drug resistance,
e.g., gives rise to methicillin resistant Staphylococcus
aureus, MRSA.
The proposed mechanism suggests pharmaceutical design strategies
for overloading the capacity of two molecules of ATP to open
access to the channel for export. Structural homology of Staphylococcus
aureus, Sav 1866, to human P-glyco- protein and MRP2,
suggests a similar mechanism could be relevant to human carcinoma
cells.
The transport mechanism utilizes two thermodynamic quantities
- ΔGHA, the change in
Gibbs free energy for hydrophobic association, and ΔGap,
an apolar-polar repulsive free energy for hydration, derived
from studies on designed elastic-contractile model proteins
(ECMPs). These quantities also allow design of remarkably
biocompatible ECMPs as drug delivery vehicles with remarkable
control of release profiles and of ECMPs that provide the
means of developing pharmaceuticals for blocking multi-drug
resistance.
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