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Cardiovascular
& Hematological Disorders - Drug Targets
ISSN: 1871-529X
Current Drug Targets - Cardiovascular
& Hematological Disorders
Volume 7, Number 4, December 2007
Contents
Relevance of the Vascular Effects of Insulin in the
Rationale of its Therapeutical Use Pp. 228-249
Giovanni Anfossi, Isabella Russo, Gabriella Doronzo and Mariella
Trovati
[Abstract]
The Ubiquitin-Proteasome System and Proteasome Inhibitors
in Central Nervous System Diseases Pp. 250-273
Imtiaz M. Shah and Mario Di Napoli
[Abstract]
Variability in Individual Responsiveness to Aspirin:
Clinical Implications and Treatment Pp. 274-287
Isabel Coma-Canella and Amelia Velasco
[Abstract]
The Effect of Cannabis sativa L. (Hemp Seed)
on Hematological Parameters in Guinea Pigs Pp. 288-290
Isaac Karimi, Hossein Hayatghaibi, Javad Yousefi, Adel
Saberivand and Saeed Zavareh
[Abstract]
Xanthine Oxidase Inhibitors the Unappreciated Treatment
for Heart Failure Pp. 291-294
Myrvin H. Ellestad
[Abstract]
Role of PI3 Kinase Gamma in Excitation-Contraction
Coupling and Heart Disease Pp. 295-304
Gavin Y. Oudit and Zamaneh Kassiri
[Abstract]
Abstracts
[Back to top]
Relevance of the Vascular Effects of Insulin in the
Rationale of its Therapeutical Use
Giovanni Anfossi, Isabella Russo, Gabriella Doronzo and Mariella
Trovati
Beyond carbohydrate, lipid and protein metabolism, insulin
influences hemostasis, vascular tone and angiogenesis. Insulin
per se causes a slow-acting vasodilation selectively occurring
in skeletal muscle tissue, mainly related to an endothelium-dependent
mechanism. Insulin-induced vasodilation is attenuated by the
secretion of endothelin-1 and by the stimulation of sympathetic
activity. The direct vasodilating effect of insulin is deeply
reduced in the insulin-resistant states. The insulin effects
on platelet aggregation and inflammatory response are attributable
to increased synthesis of nitric oxide, and are deeply reduced
in the insulin-resistant states. Furthermore, insulin reduces
oxidative stress and promotes angiogenesis and proliferation
of vascular smooth muscle cells. The involvement of insulin
signalling pathways in these different insulin actions both
in insulin sensitive and in insulin resistant states and the
concept of “selective insulin resistance” are
discussed.
The vascular effects of insulin are generally ignored in the
clinical practice, despite the evidences that insulin infusion
with algorithms aiming to provide an optimal blood glucose
control improves the clinical outcomes of patients with severe
acute illness and myocardial infarction. Aim of this review
is to clarify whether the vascular effects of insulin could
represent a new “rationale” for its therapeutical
use, independently of the well known metabolic actions.
[Back to top]
The Ubiquitin-Proteasome System and Proteasome Inhibitors
in Central Nervous System Diseases Pp.
Imtiaz M. Shah and Mario Di Napoli
The ubiquitin-proteasome system (UPS) displays an important
quality control function, by removing abnormal proteins from
the cytosol, the nucleus and the endoplasmic reticulum. It
controls the intracellular levels of short-lived and regulatory
proteins important for a variety of basic cellular processes.
The pathway involves an enzymatic cascade through which multiple
76–amino acid ubiquitin monomers are covalently attached
via a three-step process to the protein substrate,
which is then degraded by the 26S proteasome complex. The
proteasome is a cylindrical organelle that recognizes ubiquitinated
proteins, degrades a large proportion of intracellular proteins,
and recycles ubiquitin. Alterations in the proteasome proteolytic
pathway have been contributed to protein alterations associated
with aging and, in fact, dysregulation of the UPS has been
linked to several disease states including neurodegenerative
diseases, malignancies, and inflammatory-related diseases.
Strong preclinical data now exist supporting the use of reversible
proteasome inhibitors to treat a variety of disease states
including cancer, autoimmune and inflammatory diseases, myocardial
infarction, and ischemic brain injury. Bortezomib (Velcade®)
has recently been licensed for the treatment of patients with
multiple myeloma and is also undergoing further evaluation
for the treatment of chronic lymphocytic leukemia and a variety
of solid tumors. MLN-519 is a small-molecular-weight lactacystin
analogue and is being studied for the potential treatment
of inflammatory disease and stroke. MLN-519 has demonstrated
a neuroprotective effect in rat models of middle cerebral
artery occlusion reducing infarct volume, brain oedema and
improves neurological outcome with a therapeutic window of
up to 6-hrs. This review article focuses on the recent progress
in the use of proteasome inhibitors in nervous system diseases
with emphasis on the bench-to-bedside research effort which
provided the foundation for clinical development of proteasome
inhibitors in the treatment of neurological disorders.
[Back to top]
Variability in Individual Responsiveness to Aspirin: Clinical
Implications and Treatment
Isabel Coma-Canella and Amelia Velasco
Aspirin protects from cardiovascular events because of
its antiaggregant effect. The occurrence of new events in
patients who take aspirin has been called clinical aspirin
resistance. Many authors believe that aspirin resistance must
be detected by biochemical tests, although there is no agreement
on which is the best. Nor is there agreement on the term aspirin
resistance. Tests used in research laboratories are aggregometry
(turbidometric and impedance), tests based on activation-dependent
changes in platelet surface, and tests based on activation-dependent
release from platelets. Point-of-care tests are PFA-100, IMPACT
and VerifyNow, which can detect platelet dysfunction that
may be due to aspirin effect, but their use for this purpose
is not yet recommended. Aspirin response may be modified by
different factors: patient’s compliance, dose, smoking,
hyperlipidemia, hyperglucemia, acute coronary syndrome, percutaneous
revascularization, recent stroke, extracorporeal circulation,
heart failure, exercise, circadian rhythm, absorption, concomitant
medications, polymorphisms. Patients with aspirin resistance
may have an increased risk of cardiovascular events, and possible
therapeutic options are to increase the dosage, to replace
aspirin with another antiaggregant drug or to add another
drug. In conclusion, there are many reasons that explain the
variability in individual responsiveness to aspirin. The term
resistance is probably not exact in describing this phenomenon.
[Back to top]
The Effect of Cannabis sativa L. (Hemp Seed) on Hematological
Parameters in Guinea Pigs
Isaac Karimi, Hossein Hayatghaibi, Javad Yousefi, Adel
Saberivand and Saeed Zavareh
The objective of this study was to investigate the effect
of ingestion of powder of hemp seed on blood picture. This
study was experienced on five guinea pigs that fed with normal
diet (fresh vegetable and tab water), in addition were force-fed
5 g/kg/day of the powder of hemp seed for 60 days by means
of an endogastric tube and syringe. At the beginning day and
the termination of study day-60 the blood was taken from animals
and the erythrocyte number, leukocyte number, packed cell
volume (PCV), and hemoglobin concentration values were determined.
The result on analysis showed that erythrocyte-count and PCV
significantly decreased (p < 0.05) whereas hemoglobin concentration
and leukocyte number values showed a steady decline which
was not significant (P > 0.05). None of the values fell
below the normal physiological range of the experimental animals.
This shows that hemp seed which contains tetrahydrocannabinols
as its active constituents has long term significant toxicological
implication such as bone marrow suppression with respect to
the concentration given on the erythrocytes of mammals. It
is recommended that individuals who have anemia or immunity
complication should not use hemp seed in their food preparation
on regular basis.
[Back to top]
Xanthine Oxidase Inhibitors the Unappreciated Treatment for
Heart Failure
Myrvin H. Ellestad
The recognition that uric acid plays a significant role
in cardiac function has been slow to be appreciated. About
50 years ago it was recognized that gout and high uric acid
levels were often a marker for coronary heart disease, Since
then the literature has contained several hundred studies
which have demonstrated a great deal of the physiology of
xanthine oxidase inhibition.
A reduction in xanthine oxidase improves cardiac output, improves
endothelial function, reduces myocardial infarct size, reduces
inflammation, reduces myocardial oxidative stress and platelet
adhesiveness.
It seems logical that these effects would be beneficial to
patients with congestive heart failure. A large placebo controlled
trial with Allopurinol seems very likely to demonstrate that
this old fashioned drug provides a new found benefit.
[Back to top]
Role of PI3 Kinase Gamma in Excitation-Contraction Coupling
and Heart Disease
Gavin Y. Oudit and Zamaneh Kassiri
Class I phosphoinositide 3-kinases (PI3Ks) are enzymes
with both protein and lipid kinase activities that have ubiquitous
cellular functions. In the heart, subclass IA PI3Ks, PI3K-α
and beta, regulate cell growth, apoptosis, cell division
and cell size, whereas PI3Kgamma, the only member of subclass
IB, has been shown to regulate myocardial contractility. Loss
of p110γ,
the catalytic subunit of PI3Kγ,
enhances cardiac excitation-contraction coupling by modulating
cyclic adenosine monophosphate (cAMP) levels in subcellular
domains containing the sarcoplasmic reticulum (SR) leading
to increased cAMP-mediated phosphorylation of phospholamban.
The ability of p110γ
to modulate cAMP is likely mediated by the protein-protein
interactions with the cAMP-degrading enzymes, phosphodiesterases,
independent of its lipid kinase activity. PI3Kγ
also plays a key role in modulating the cAMP response and
desensitization of beta-adrenergic receptors. Loss of p110γ
gamma leads to acute decompensation and rapid progression
into heart failure in response to pathological biomechanical
stress while lipid kinase-dead mutants were relatively resistant
suggesting that elevated intracellular cAMP (and its secondary
effects) is an important predisposing factor for heart failure.
The commercial availability of specific PI3Kγ
inhibitors may be used as therapeutic agents in inflammatory
and cardiovascular diseases. In this review article, we discuss
the key role of PI3Kγ
gamma in regulating cAMP, Ca2+
cycling, β-adrenergic
signaling and myocardial structure and function in heart disease.
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