Redox Signaling, Oxidative Stress in Cardiovascular Disease –basic Science and Clinical Aspects
Page: 1-24 (24)
Author: Bashir Matata* and Maqsood Elahi
DOI: 10.2174/9789815165012123010004
PDF Price: $15
Abstract
The generation of certain species of biomolecules described as reactive oxidant species (ROS e.g., superoxide, O2 -; hydrogen peroxide, H2O2; hydroxyl radicals (OH.)) and reactive nitrogen species (RNS e.g., peroxynitrite, OONO-; nitric oxide, •NO) is a critical step in health and disease . These species play critical roles in cell defences in both animals, and plants. They also perform an important function in the regulation of key cellular signalling pathways such as cell differentiation, proliferation, migration, and apoptosis (commonly described as redox signalling pathways). The imbalance between the levels of ROS and RNS generated to that of antioxidant species may lead to oxidative stress and biomolecular damage, especially in situations where the latter are depleted. Redox biology and oxidative stress are particularly important in ischaemia-reperfusion associated diseases in particular the pathogenesis of cardiovascular disease (CVD). CVD is a major cause of mortality on a global scale, although the exact mechanisms underlying the pathological process are not fully understood. It is believed that ROS play a pivotal role in the progression of CVD. In particular, recent evidence suggests that the development of atherosclerosis is modulated by ROS and influenced by other factors such as inflammatory responses, disturbed blood flow, and arterial wall remodelling. This chapter provides an overview of the pathways of oxidative stress and redox-regulated signalling underlying the genesis and progression of cardiovascular disease.
Oxidative Stress and Leukocytes Activation - The Two Keystones of Ischemia/Reperfusion Injury during Myocardial Infarction, Valve Disease, and Atrial Fibrillation
Page: 25-44 (20)
Author: Bashir Matata* and Maqsood Elahi
DOI: 10.2174/9789815165012123010005
PDF Price: $15
Abstract
Oxidative stress is a major contributor to ischaemia reperfusion injurymediated myocardial infarction. Coronary ischemia deprives the heart muscles of nutrients and oxygen in the areas away from the site of arterial blockage, rendering cardiomyocytes unable to utilise aerobic metabolism to support their energy requirements. Homeostatic intracellular signalling systems, such as the hypoxiainducible factor (HIF) transcription factor cascade, sense the low oxygen environment. This in turn stimulates the upregulation of numerous compensatory mechanisms which are ultimately involved in elevating anaerobic glycolysis and promoting angiogenesis and vascularization. The increased anaerobic metabolism increases the production of lactic acid hence metabolic acidosis. This leads to myocyte death and the expansion of the size of the original area of the infarct. Under normal aerobic conditions, the myocardium generally metabolises relatively high levels of adenosine triphosphates (ATP). In contrast, during ischemia, the shift in energy production to glycolysis results in the inefficient production of ATP and constitutes a pathological feature, and if not reversed early, it may lead to complications such as heart failure and ischemia-induced atrial or ventricular fibrillation. Despite the widespread use of fibrinolytic agents and new types of angioplasty procedures for the treatment of myocardial infarction, often new sets of complications persist. These include the occurrence of extensive tissue injury caused by myocardial reperfusion through the reintroduction of oxygen to the previous ischemic tissues because of the excessive generation of reactive oxygen species (ROSs) and depletion of antioxidants. Widespread production of ROS damages the plasma membrane and stimulates the release of various proinflammatory agents. Several proteins become denatured for example receptors, ionic channels, transporters, or components of transduction pathways through oxidation by ROS. Altered protein structure inhibits their functions leading to the disruption of vital cellular processes. The onset of reperfusion injury is further exacerbated by the activation and infiltration of the infarcted area by polymorphonuclear leukocytes (PMNs). Several studies have identified the release of different leukocyte intracellular factors during PMN activation such as selectins and b2-integrins to be related to the magnitude of tissue damage. Some studies have shown that antagonists for leukocytes intracellular factors such as selectins abrogate PMN activation and reduce the infarct size.
More recent publications have shown that PMN activation is closely linked to the activation of other cells involved in the inflammatory response. For example, during myocardial ischemia–reperfusion injury, it has been shown that the activity of neutrophils is also modulated by lymphocytes and macrophages. This chapter summarises the interaction between oxidative stress, activation of different leukocytes and the release of factors involved in the generation of reperfusion injury.
Lipids, Oxidation, and Cardiovascular Disease
Page: 45-64 (20)
Author: Priscilla Day-Walsh*
DOI: 10.2174/9789815165012123010006
PDF Price: $15
Abstract
Cardiovascular disease (CVD) remains one of the leading causes of
morbidity and mortality worldwide with altered lipid metabolism as an important risk
factor. In the current chapter we discuss processes involved in lipid metabolism, the
past and emerging roles of various lipoprotein cholesterol molecules in this process,
free fatty-acid metabolism and the various mechanisms of lipid oxidation and their
impact on vascular physiology in health and disease. We further describe the role of
reverse cholesterol transport (RCT) in the elimination of lipids as bile acids, and finally
discuss current clinical interventions based on emerging technologies against
dyslipidemia, hypertriglyceridemia, and CVD
Maternal Factors and the Placenta: A Programming Environment for Cardiovascular Disease
Page: 65-89 (25)
Author: Wai Lok Whitney Ching, Priscilla Day-Walsh and Amanda Sferruzzi-Perri*
DOI: 10.2174/9789815165012123010007
PDF Price: $15
Abstract
The risk of chronic diseases such as cardiovascular diseases (CVD) during
postnatal life is not only determined by environmental factors in adulthood but also by
intra-uterine and early life environment according to the Developmental Origins of
Health and Disease (DOHaD) concept. Environmental insults including poor nutrition,
oxygen availability, maternal stress, alcohol, smoking and drugs, can compromise the
maternal uterine and lactational environment leading to short- and long-term
adaptations in offspring physiology or programming. While short-term predictive
adaptive responses may offer immediate survival value, they can lead to irreversible
changes in embryonic/fetal tissues and organs mediated through changes in cellular
signalling and metabolic pathways, as well as endocrine axes governing whole-body
function. The capacity for developmental adaptation may also be determined by both
genetic susceptibility and epigenetic mechanisms, as well as environmentally induced
changes in maternal microbiome structure and composition. Basic mechanisms
involved in the development of CVD have been described in previous chapters. Here
we will focus on how mechanisms involved in developmental programming may
contribute to CVD in adulthood.
The Emerging Role of Microbiome in Cardiovascular Diseases
Page: 90-111 (22)
Author: Emad Shehata and Priscilla Day-Walsh*
DOI: 10.2174/9789815165012123010008
PDF Price: $15
Abstract
Cardiovascular disease (CVD) has become one of the leading causes of poor
lifelong health and well-being. Meanwhile, the microbiome has emerged as one of the
key determinants of human cardiometabolic homeostasis and the risk of CVD. While
the clustering of the microbiome into phylum ratios or enterotypes has been correlated
to specific disease phenotypes and population characteristics, the composition of a
typical ‘healthy human microbiome’ is yet to be defined. Several population-based
studies have shown an association between certain microbial species with CVD,
although the inconsistencies have made the interpretation of such associations very
difficult as it is not possible to pinpoint microbial populations associated with CVD.
However, here we discuss current evidence on the role of the microbiome and its
metabolites on the risk of CVD. We further explore current clinical studies
investigating prebiotics and probiotics as potential therapeutic targets to modulate the
microbiome for the benefit of the host to prevent cardiometabolic diseases. We
highlight that further work to understand the role of specific species/sub-species,
strains and polymorphisms within those strains, as well as microbial gene expression
profiles and their respective metabolites is required. Coupled with high-resolution
metagenomics and metabolomics as well as a unified approach in characterising
common gut microbial communities based on global population observations, this
would provide better indicators of disease phenotype and a better framework for a
divergence to dysbiosis. The challenges that will need to be overcome in order to
define a healthy microbiome and advance the clinical use of prebiotics and probiotics
as well as faecal microbiota transplantation will also be discussed.
Oxidants and Antioxidants Interplay in the Modulation of Inflammation and Cardiovascular Disease
Page: 112-127 (16)
Author: Bashir Matata* and Maqsood Elahi
DOI: 10.2174/9789815165012123010009
PDF Price: $15
Abstract
Oxidative stress and inflammation are parallel self-perpetuating
mechanisms that when triggered, appear to be strongly linked with several
complications of cardiovascular disease (CVD). Unchecked production of reactive
oxygen species (ROS) and reactive nitrogen species (RNS) are largely the responsible
factors that operate via the activation of several transcriptional messengers and a series
of inflammatory pathways. Such messengers include Nuclear Factor-KappaB, known
to contribute to a plethora of pathological complications such as endothelial
dysfunction, the initiation and progression of atherosclerosis, irreversible ischemic
reperfusion injury, and arrhythmias, particularly atrial fibrillation. Although much is
known about the link between oxidative stress and CVD, the development of direct
therapeutic interventions has remained elusive. In experimental animal models, the use
of antioxidants in the form of dietary supplements has been shown to quench
ROS/RNS or catalyse the break-up of free radical chains and has resulted in some
measure of success. However, these findings have not been able to be replicated in
human clinical trials for several different well-known agents, such as vitamin E and
beta-carotene. Many potent naturally occurring antioxidants have been exploited by
nature such as the oxygenated carotenoids (xanthophylls) and researchers have tested
several of them in their natural form in clinical trials but sadly many of them have not
translated into useful therapeutic tools. Questions, therefore, remain as to whether the
reasons may be solely the inability to find the “right” compound(s) or delivery strategy,
or the exact mechanisms of action of existing compounds have unknown targets or
whether correct dosages are used. This chapter reviews existing evidence on the thesis
that antioxidant/anti-inflammatory compounds may present an opportunity for the
development of future therapeutic agents for both cardiovascular oxidative stress and
inflammation.
Prevention of Reperfusion Injury in Acute Myocardial Infarction: A “flashback” Journey of Novel Strategies Based on the Potential Therapeutic Role of Antioxidants
Page: 128-147 (20)
Author: Francisco Salazar-Cornejo, Abraham Gajardo, Marcelo J. Kogan and Ramón Rodrigo*
DOI: 10.2174/9789815165012123010010
PDF Price: $15
Abstract
It has been recognized that oxidative stress plays a key role in the
development of cardiac alterations derived from events of ischemia followed by
reperfusion, such as in the clinical setting of acute myocardial infarction of patients
subjected to coronary angioplasty. During ischemia, due to the occlusion of a coronary
branch, biochemical events responsible for anaerobic metabolism, ATP availability and
impairment of cell ionic homeostasis are the major deleterious effects. Following the
onset of reperfusión, a burst of reactive oxygen species occurs, thus accounting for
increased tissue damage due to the endovascular intervention. This iatrogenic damage
has not been adequately treated to date. Among the many pharmacological attempts,
cardioprotection with antioxidants should be mentioned; however, the experimental
studies have not been translated into successful clinical trials aimed to prevent this
enhancement of cardiac damage, despite some beneficial effects have been reported in
the clinical outcome of the patients. This chapter aimed to present the hypothesis that
the combination of antioxidant effects should improve the cardioprotection of the
patients subjected to coronary angioplasty following acute myocardial infarction.
Therefore, we present an update of previous attempts at cardioprotection with an
antioxidant alone and give the basis for the expected improved protection by using two
or more antioxidant compounds exerting different mechanisms that could enhance the
beneficial protective effect.
Improvement of Nitric Oxide Availability in Myocardial Ischemia/reperfusion: Role of Nanotechnology as a Therapeutic Approach
Page: 148-166 (19)
Author: Marcelo J Kogan*, Francisco Salazar-Cornejo, Abraham Gajardo and Ramón Rodrigo*
DOI: 10.2174/9789815165012123010011
PDF Price: $15
Abstract
In the search for an effective treatment against myocardial damage caused
by oxidative stress, it has become necessary to generate new therapies that overcome
the difficulties and failures observed in conventional therapies. Therefore,
nanotechnology and nanoparticle development may open new horizons for the control
and therapy of oxidative stress and associated myocardial damage. The term
nanomaterials describe materials with nanoscale dimensions (< 100 nm). In this
chapter, different nanoparticle drug delivery systems, along with their targeting
strategies, and how they can help to improve therapeutic failure in oxidative stress
using nanoparticles in the control of myocardial infarction and oxidative stress will be
discussed. Achieving an inhibition of oxidative stress producers or improving the
endogenous antioxidant capacity through drug delivery by nanoparticles increases the
drug’s aqueous solubility, protects its degradation, allows prolonged release, and
improves the bioavailability, determining a targeted delivery, and decreases the toxic
side effects. It leads to new therapeutic opportunities for both monotherapies and
combined therapies, benefiting from nanoparticles' particularities associated with
increased solubility, bioavailability, and specificity.
Subject Index
Page: 167-171 (5)
Author: Bashir Matata, Maqsood Elahi and Priscilla Day-Walsh
DOI: 10.2174/9789815165012123010012
Introduction
Blood Oxidant Ties: The Evolving Concepts in Myocardial Injury and Cardiovascular Disease is an update on the recent advances in the development of antioxidant-based therapies. It starts with an overview of the mechanisms underlying the genesis of oxidative stress, summarizing the link between oxidative stress and a number of cardiovascular conditions. This is followed by an explanation of how oxidative stress interacts with lipid metabolism and the placental environment. Three chapters on the role of antioxidant-based therapy for cardiovascular diseases round up the book. Key Features - Outlines several cell-signaling pathways that are modulated by the interplay between reducing and oxidizing agents (redox status) and gene expression in the cardiovascular disease process - Brings information about maternal programming environment in the placenta - Covers development of novel nanotechnology-based antioxidant delivery systems for effective drug delivery - Includes references for further reading The book is aimed at a broad readership of scientific and medical professionals involved in research on cardiovascular diseases, pathophysiology, pharmacy, pharmaceutical science and life sciences. It also serves as a reference for scholars who want to understand the complex biochemical mechanisms of antioxidant agents.