Current Drug Targets - Cardiovascular & Haematological Disorders, Volume 3, Number 3, 2003
Contents
The Heme Oxygenase System: Its Role in Liver
Inflammation
Pp.199-208
Richard F.
Potter and Christian Wunder
Novel Immunotherapeutic Strategies for
Invasive Fungal Disease Pp.209-217
A.B. van Spriel
Coronary Atherosclerotic Disease Burden: An
Emerging Endpoint in Progression / Regression Studies Using Intravascular
Ultrasound
Pp.218-226
Paul Schoenhagen and Steven E. Nissen
Molecular Diversity of the Developing and
Adult Myocardium: Implications for Tissue Targeting Pp.227-239
Mar’a del Pilar de Castro, Lourdes Acosta, Jorge N. Dom’nguez, Amelia Ar‡nega and Diego Franco
The Role of Neuropeptides and Neurohormones
in Neurogenic Cardiac Arrhythmias Pp.240-253
T.M. Saleh
Hypoxia-Inducible Factor-1: A Molecular Hint
of Physiological Changes in the Carotid Body During Long-Term Hypoxemia? Pp.254-259
Man-Lung Fung
Abstracts
[Back to top] The
Heme Oxygenase System: Its Role in Liver Inflammation
Richard F.
Potter and Christian Wunder
Heme Oxygenase is the rate-limiting enzyme in the degradation of heme into carbon monoxide (CO), iron and bilirubin. To date, three heme oxygenase isozymes have been identified: HO-1, HO-2 and HO-3. While HO-1 is structurally different from its counterparts, HO-2 and HO-3 are very similar (90% homology), with HO-3 being a poor heme catalyst. Of the three isozymes, HO-1 is believed to be the only inducible form. Constitutively expressed HO-2 has been identified in several organs including kidney and vascular smooth muscle, with the most abundant sources (and activity) being in the liver, brain, spleen and testes. Within the normal liver, HO-2 is constitutively expressed within hepatocytes, Kupffer cells, endothelial cells and Ito cells.
Until recently, products of the HO reaction were regarded as potentially toxic waste destined only for excretion. However, this view is changing as evidence suggests that HO activity plays an important protective role against cellular stress during inflammatory diseases. Biliverdin is reduced to bilirubin, which has been shown to possess potent antioxidative properties. CO, which is produced in equimolar concentrations to biliverdin and ferrous iron during heme oxidation by HO, may function as a second messenger stimulating soluble guanylate cyclase (sGC) and regulating vascular tone in combination with the free radical gas NO. CO may also possess anti-inflammatory properties such as the capacity to inhibit platelet aggregation, or the expression of pro-inflammatory cytokines. Recently, it has been shown that CO regulates bile formation and bile flow. We review the functional role of HO in liver and the potential application of HO-1 in therapeutic approaches to the treatment of inflammation
[Back to top] Novel Immunotherapeutic Strategies for
Invasive Fungal Disease
A.B. van Spriel
Infectious diseases still represent a major cause of mortality in man. Failure of the immune system to eradicate pathogens may result in serious invasive infections. Increasing numbers of immunocompromised patients, ineffective treatment and the emergence of drug-resistant pathogens represent the underlying problems. The focus of this review is on the pathogenesis of systemic fungal disease and the development of novel immunotherapeutic approaches. A comprehensive understanding of host-pathogen interactions is required for manipulation of immune responses to direct anti-fungal immunity. The potential of growth factor- and antibody-based therapeutics for invasive
fungal disease are discussed. Recent advances in antibody technology may provide new strategies for developing antibody-based anti-fungal therapies. Development of fungal disease is related primarily to impaired host defense mechanisms, which emphasizes the importance of immunorestorative therapy in immunocompromised individuals. Controlled comparative clinical research is needed to evaluate the efficacy of novel immunotherapies, which provide prospects for the future management of invasive fungal disease.
[Back to top] Coronary Atherosclerotic Disease Burden: An
Emerging Endpoint in Progression / Regression Studies Using Intravascular
Ultrasound
Paul
Schoenhagen and Steven E. Nissen
Coronary artery disease (CAD) represents the major cause of mortality in North America and Western Europe. Most acute coronary events, including myocardial infarction (MI) and sudden cardiac death, are initiated by the sudden rupture of mildly stenotic but vulnerable lesions and subsequent thrombosis. Recent results demonstrate a high prevalence of such plaques many years before clinical events occur. Because the event rate in asymptomatic patients, which would be candidate for primary prevention, is relatively low, pharmacological studies with the endpoint of MI and death require large study populations and long follow-up.
Alternatively, the direct observation of coronary plaque burden and morphology with in vivo imaging modalities has been proposed as an endpoint in serial studies. This review will summarize the rational of this approach and describe the use of intravascular ultrasound (IVUS) for such studies.
[Back to top] Molecular Diversity of the Developing and
Adult Myocardium: Implications for Tissue Targeting
Mar’a del Pilar
de Castro, Lourdes Acosta, Jorge N. Dom’nguez, Amelia Ar‡nega and Diego Franco
The heart is the first functional embryonic organ. During embryogenesis the development of the heart and its vasculature is a complex process that give rise to the formation of four-chambered heart with a synchronously contraction, from a single tubular heart with a peristaltic contraction. The spectacular progress of modern developmental biology has marked the beginning of a new era in embryology. Over the last years, several families of genes with restricted cardiac expression have been identified including genes such as those encoding for tissue-specific transcription factors, contractile proteins, as well as, more recently, ion channels.
In this review, we illustrate the heterogeneity of the developing and adult myocardium in mice. Looking at the expression profile of transcription factors and contractile proteins, it can be seen that the tubular heart is patterned along the three embryonic axes, antero/posterior, dorso/ventral and left/right, besides having several genes that are expressed homogeneously within the entire myocardium. In the embryonic heart, two new types of pattern arise, chamber-specific and systemic/pulmonary gene expression, while within the foetal and adult heart, a wider heterogeneity is observed, not only between the working myocardium and the specialized cardiac conduction system but also within distinct myocardial chambers, specially in the atrial components. Such heterogeneity is also observed if one looks at the electrophysiological characteristics of the developing myocardium and their underlying molecular components. Several evidences support the notion that the distinct expression profiles observed in mice can be extrapolated to humans. Thus, these data reveal that the molecular diversity of the myocardium should be taken into account on the design of drug targets as well as on gene and cell therapy approaches.
[Back to top] The Role of Neuropeptides and Neurohormones in Neurogenic Cardiac
Arrhythmias
T.M. Saleh
The functional significance of neuropeptides and neurohormones throughout the neuroaxis has been the focus of considerable research over the past 25 years. These “gut peptides” or “reproductive hormones” have been localized within nuclei responsible for the relay of visceral afferent information to the forebrain. The presence of peptides and hormones along the gut- or heart-brain continuum suggests that these neurochemicals do more than modulate the visceral processes of digestion and reproduction respectively. Numerous studies have shown that the exogenous administration of these neurochemicals directly into visceral afferent nuclei significantly alters blood pressure, heart rate, autonomic tone and the sensitivity of the baroreceptor reflex (an index of sympatho-vagal balance). A strong inverse correlation has been demonstrated between the sensitivity of the baroreceptor reflex and susceptibility to lethal cardiac arrhythmias which lead ultimately to sudden cardiac death. The differential effects of various neurochemicals on the sensitivity of the baroreceptor reflex suggests that some neurochemicals may act as preventatives while others may actually contribute to the pathogenesis of neurogenic cardiac arrhythmias. Hormones such as estrogen, in addition to their neuroprotective properties, may also play a role in modulating the cardiovascular consequences to neurogenic pathologies including stroke and epilepsy. This review will summarize the evidence available which suggests that neuropeptides and neurohormones can alter both neurogenic as well as visceral pathology-induced changes in autonomic function resulting in an increased risk of sudden cardiac death.
[Back to top] Hypoxia-Inducible
Factor-1: A Molecular Hint of Physiological Changes in the Carotid Body During
Long-Term Hypoxemia?
Man-Lung Fung
The aims of this review are to describe recent data focusing on the anatomical, functional and molecular changes of the carotid body during chronic hypoxemia, and to summarize current views in the literature relevant to the topic. The carotid body is the major peripheral sensor for detecting chemicals in the arterial blood. In acute hypoxia, carotid chemoreceptors transduce the signal to the brain for triggering reflexive responses of the cardiopulmonary system. The carotid body enlarges and changes its hypoxic sensitivity in humans and animals living at high altitude or subject to long-term hypoxemia associated with chronic cardiopulmonary diseases or hematological disorders. Recently, a surge of new evidence suggests that a heterodimeric transcriptional factor directly induced by severe tissue or cellular hypoxia, namely hypoxia-inducible factor-1 (HIF-1), is a key controller for the transcriptional regulation of the gene expression of a spectrum of proteins for the cellular response to hypoxia. These proteins, such as endothelin-1, type II nitric oxide synthase and vascular endothelial growth factor, play important physiological roles in the control of vascular tone and angiogenesis. In the carotid body, chronic hypoxemia induces remodeling of the vasculature, stimulates proliferation of the chemosensitive cells, and changes their excitability and sensitivity to chemical signals. In addition, HIF-1-targeted genes are expressed in the carotid body and the expression is modulated by chronic hypoxemia, suggesting an active role for HIF-1 in moderate levels of hypoxic stress.