Current Vascular Pharmacology, Vol. 3, No. 3, 2005
Contents
Role
of Oxidative-Nitrostative Stress and Poly(ADP-ribose) Polymerase in
Cardiovascular
Pathophysiology
Guest
Editor: Pal Pacher
Editorial
Pp.207-207
Pal Pacher
Structure
and Function of Poly(ADP-ribose) Polymerase-1: Role in Oxidative Stress-Related
Pathologies Pp.209-214
Laszlo Virag
Role
of Nitrosative Stress and Poly(ADP-ribose) Polymerase Activation in Myocardial Reperfusion
Injury Pp.215-220
Gabor Szabo and Susanne Bahrle
Role
of Oxidative-Nitrosative Stress and Downstream Pathways in Various Forms of
Cardiomyopathy and Heart Failure Pp.221-229
Zoltan Ungvari, Sachin A. Gupte, Fabio A. Recchia, Sandor
Batkai and Pal Pacher
Oxidative-Nitrosative
Stress In Hypertension Pp.231-246
Nelson Escobales and Maria J. Crespo
Role
of Nitrosative Stress and Poly(ADP-ribose) Polymerase Activation in Diabetic
Vascular Dysfunction Pp.247-252
Jon G. Mabley and Francisco Garcia Soriano
Oxidative-Nitrosative
Stress as a Contributing Factor to Cardiovascular Disease in Subjects with
Diabetes Pp.253-266
Martin J. Stevens
Role
for Poly(ADP-ribose) Polymerase Activation in Diabetic Nephropathy, Neuropathy
and Retinopathy Pp.267-283
Irina G. Obrosova and Ulrich A. Julius
Role
of Oxidative and Nitrosative Stress, Longevity Genes and Poly(ADPribose)
Polymerase in Cardiovascular Dysfunction Associated with Aging Pp.285-291
Anna Csiszar, Pal Pacher, Gabor Kaley and Zoltan Ungvari
Role
of Nitrosative Stress and Activation of Poly(ADP-ribose) Polymerase-1 in
Cardiovascular Failure Associated with Septic and Hemorrhagic Shock
Pp.293-299
Oleg V. Evgenov and Lucas Liaudet
Pharmacological
Inhibition of Poly(ADP-ribose) Polymerase in Cardiovascular Disorders: Future
Directions Pp.301-303
Csaba Szabo
Abstracts
[Back to top] Editorial
Pal Pacher
Dysregulation of nitric oxide (NO) and increased oxidative stress have been implicated in the pathogenesis of cardiac and endothelial dysfunction associated with myocardial infarction, chronic heart failure, diabetes, atherosclerosis, hypertension, aging and various forms of shock. Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide, which impairs cardiovascular function via multiple mechanisms including activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP), also known as poly(ADP ribose) synthetase (PARS). When activated by DNA single-strand breaks, PARP initiates an energy-consuming cycle by transferring ADP ribose units from NAD+ to nuclear proteins. This process results in rapid depletion of the intracellular NAD+ and ATP pools, slowing the rate of glycolysis and mitochondrial respiration, eventually leading to cellular dysfunction and death. Moreover, PARP is involved in the expression of various inflammatory genes and mediators that contribute to cardiovascular pathophysiology. Overactivation of PARP represents an important mechanism of tissue damage in various pathological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury, heart failure, stroke, shock and autoimmune b-cell destruction and diabetic complications. Recent studies have provided evidence that the neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy of various forms of cardiovascular injury. This issue focuses on the role of oxidative-nitrosative stress and PARP activation in cardiovascular disorders and on novel emerging therapeutic strategies offered by neutralization of peroxynitrite and by inhibition of the PARP in these pathological conditions.
[Back to top] Structure and
Function of Poly(ADP-ribose) Polymerase-1: Role in Oxidative Stress-Related
Pathologies
Laszlo Virag
Poly(ADP- ribosyl) ation is a reversible post-translational protein modification implicated in the regulation of a number of biological functions. Whereas an 18 member superfamily of poly(ADP-ribose) polymerase (PARP) enzymes synthesize poly(ADP-ribose) (PAR), a single protein, PAR glycohydrolase (PARG) is responsible for the catabolism of the polymer. PARP-1 accounts for more than 90% of the poly(ADP- ribosyl)ating capacity of the cells. PARP-1 activated by DNA breaks cleaves NAD+ into nicotinamide and ADP- ribose and uses the latter to synthesize long branching PAR polymers covalently attached to acceptor proteins including histones, DNA repair enzymes, transcription factors and PARP-1. Whereas activation of PARP-1 by mild genotoxic stimuli may facilitate DNA repair and cell survival, irreparable DNA damage triggers apoptotic or necrotic cell death. In apoptosis, early PARP activation may assist the apoptotic cascade [e.g. by stabilizing p53, by mediating the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus or by inhibiting early activation of DNases]. In most severe oxidative stress situations, excessive DNA damage causes over activation of PARP-1, which incapacitates the apoptotic machinery and switches the mode of cell death from apoptosis to necrosis. Besides serving as a cytotoxic mediator, PARP-1 is also involved in transcriptional regulation, most notably in the NFkB and AP-1 driven expression of inflammatory mediators. Pharmacological inhibition or genetic ablation of PARP-1 provided remarkable protection from tissue injury in various oxidative stress-related disease models ranging from stroke, diabetes, diabetic endothelial dysfunction, myocardial ischemia-reperfusion, shock, Parkinson's disease, arthritis, colitis to dermatitis and uveitis. These beneficial effects are attributed to inhibition of the PARP-1 mediated suicidal pathway and to reduced expression of inflammatory cytokines and other mediators (e.g. inducible nitric oxide synthase).
[Back to top] Role of
Nitrosative Stress and Poly(ADP-ribose) Polymerase Activation in Myocardial
Reperfusion Injury
Gabor Szabo and Susanne Bahrle
Ischemia and reperfusion injury leads to a complex pathophysiological process, which in turn results in the generation of free radicals. Peroxynitrite, a highly reactive species causes DNA single strand breaks, which activates the nuclear enzyme, poly (ADP-ribose) polymerase (PARP). The activation of PARP leads to an energy consuming inefficient repair cycle with subsequent depletion of NAD+ and ATP pools and necrotic cell death. The present review overviews the pathophysiological role of the peroxynitrite-PARP pathway in cardiac ischemia/reperfusion injury with special reference to the therapeutic potential of PARP inhibitors in the treatment of this disease.
[Back
to top] Role of Oxidative-Nitrosative Stress and
Downstream Pathways in Various Forms of Cardiomyopathy and Heart Failure
Zoltan Ungvari, Sachin A. Gupte, Fabio A. Recchia, Sandor
Batkai and Pal Pacher
Heart failure is the major cause of hospitalization, morbidity and mortality worldwide. Previous experimental and clinical studies have suggested that there is an increased production of reactive oxygen species (ROS: superoxide, hydrogen peroxide, hydroxyl radical) both in animals and in patients with acute and chronic heart failure. The possible source of increased ROS in the failing myocardium include xanthine and NAD(P)H oxidoreductases, cyclooxygenase, the mitochondrial electron transport chain and activated neutrophils among many others. The excessively produced nitric oxide (NO) derived from NO synthases (NOS) has also been implicated in the pathogenesis of chronic heart failure (CHF). The combination of NO and superoxide yields peroxynitrite, a reactive oxidant, which has been shown to impair cardiac function via multiple mechanisms. Increased oxidative and nitrosative stress also activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP), which importantly contributes to the pathogenesis of cardiac and endothelial dysfunction associated with myocardial infarction, chronic heart failure, diabetes, atherosclerosis, hypertension, aging and various forms of shock. Recent studies have demonstrated that pharmacological inhibition of xanthine oxidase derived superoxide formation, neutralization of peroxynitrite or inhibition of PARP provide significant benefit in various forms of cardiovascular injury. This review discusses the role of oxidative/nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure.
[Back to top] Oxidative-Nitrosative Stress In Hypertension
Nelson Escobales and Maria J. Crespo
Reactive oxygen species (ROS) are important signaling molecules in the vasculature. However, when there is imbalance between their occurrence and antioxidant defense mechanisms, ROS can contribute to the vascular abnormalities that lead to hypertension. Evidence accumulated in the last decade strongly supports the notion that ROS are generated in the vasculature mainly by NAD(P)H oxidase in a mechanism that is angiotensin II-dependent. Activation of this enzyme leads to superoxide production and uncouples endothedial NO synthase (eNOS), which sustains oxidative stress while increasing the levels of tissue-damaging peroxynitrite. The latter can result in vascular dysfunction. NAD(P)H-dependent ROS formation, in particular H2O2, could also contribute to vascular injury by sustaining NAD(P)H oxidase activation, promoting inflammatory gene expression, extracellular matrix reorganization, and growth (hypertrophy/hyperplasia) of vascular smooth muscle cells. The effect of ROS appears to be mediated by redox-sensitive targets such as tyrosine kinases and phosphatases, mitogen-activated protein kinases, transcription factors, matrix metalloproteinases, peroxisome proliferator activated receptor-a, poly(ADP-ribose)polymerase-1, Ca2+ signaling mechanisms and secreted factors such as cyclophilin A and heat shock protein 90-a. Redox-sensitive targets appear to play a central role in normal vascular function, but can also lead to remodeling of the vascular wall, increasing vascular reactivity and hypertension. Polymorphisms in the p22phox gene promoter could determine susceptibility to NAD(P)H-mediated oxidative stress in humans and animals with hypertension. Although ROS are strongly implicated in the etiology of hypertension, clinical trials with antioxidants are inconclusive regarding their effectiveness in treating the disease. New drugs with both antihypertensive action and antioxidant properties (Celiprolol, Carvedilol) offer promising results in the management of hypertension.
[Back to top] Role
of Nitrosative Stress and Poly(ADP-ribose) Polymerase Activation in Diabetic
Vascular Dysfunction
Jon G. Mabley and Francisco Garcia Soriano
Complications of diabetes rather than the primary disease itself pose the most challenging aspects of diabetic patient management. Diabetic vascular dysfunction represents a problem of great clinical importance underlying the development of many of the complications including retinopathy, neuropathy and the increased risk of stroke, hypertension and myocardial infarction. Hyperglycaemia stimulates many cellular pathways, which result in oxidative stress, including increased production of advanced glycosylated end products, protein kinase C activation, and polyol pathway flux. Endothelial cells produce nitric oxide constitutively to regulate normal vascular tone; the combination of this nitric oxide with the hyperglycaemia-induced superoxide formation results in the production of reactive nitrogen species such as peroxynitrite. This nitrosative stress results in many damaging cellular effects, but it is these effects on DNA, which are the most damaging to the cell function; nitrosative stress induces DNA single stand breaks and leads to over-activation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP). PARP activation contributes to endothelial cell dysfunction and appears to be the central mediator in all the mechanisms by which hyperglycaemia-induces diabetic vascular dysfunction. This review focuses on the mechanism by which hyperglycaemia induces nitrosative stress and the role PARP activation plays in diabetic vascular dysfunction.
[Back to top] Oxidative-Nitrosative
Stress as a Contributing Factor to Cardiovascular Disease in Subjects with
Diabetes
Martin J. Stevens
In diabetes, clear evidence has emerged for the presence of oxidative-nitrosative stress, which may be a consequence of a glucose-mediated imbalance of systemic antioxidant buffering capacity, coupled with increased production of free radical species. Although multiple metabolic pathways have been identified, which may contribute to oxidative stress in diabetes, the principal pathogenetic pathways and their key down-stream targets remain to be established. Evidence links oxidative stress in particular, to elevations of postprandial glucose and lipids, which also have recently emerged as major risk factors for cardiovascular events. Indeed, considerable evidence suggests that increased oxidative stress in diabetes may play an important role in the development or progression of cardiovascular disease by a number of different mechanisms, including alterations of cardiovascular sympathetic nervous system tone and integrity, elevation of acute phase reactants, disruption of endothelial function and facilitation of myocardial injury. Despite the disappointments of recent large scale clinical trials evaluating the efficacy of antioxidants in cardiovascular disease, many therapeutic agents which have been used successfully in diabetic subjects at high risk for cardiovascular disease have a mechanism of action which includes an antioxidant capacity. Therefore, incorporating an antioxidant action in future therapeutic approaches to combat cardiovascular disease complicating diabetes, appears to remain justified and warrants further evaluation.
[Back to top] Role for Poly(ADP-ribose)
Polymerase Activation in Diabetic Nephropathy, Neuropathy and Retinopathy
Irina G. Obrosova and Ulrich A. Julius
Chronic complications of diabetes mellitus e.a. diabetic nephropathy, neuropathy and retinopathy develop in at least 30-50% of patients with both Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes, and are the major cause of increased morbidity and mortality. The ultimate consequences of diabetes complications include renal failure, foot ulceration and amputation, and blindness. The magnitude of the problem and its economic impact make extremely important to understand the natural history of chronic diabetes complications and to identify more successful preventive and therapeutic options. The pathogenesis of diabetes complications involves multiple mechanisms. The importance of vascular component is well recognized in diabetic retinopathy, which is primarily a vascular disease, as well as diabetic nephropathy developing as a result of complex interplay between hemodynamic and metabolic factors. The importance of vascular versus non-vascular mechanisms in the pathogenesis of diabetic neuropathy remains a subject of debate. Studies in animal and cell culture models revealed that such mechanisms as increased aldose reductase activity, non-enzymatic glycation/glycoxidation, activation of protein kinase C, impaired growth factor support, enhanced oxidative/nitrosative stress, and its downstream effectors such as mitogen-activated protein kinase activation, inflammatory response, endothelin-1 overexpression and impaired Ca++ signaling, play an important role in all three tissue-targets for diabetes complications i.e. kidney, retina and peripheral nerve. Evidence for important role of the downstream effector of free radical and oxidant-induced DNA injury, poly(ADP-ribose) polymerase activation, is emerging. This review describes recent studies addressing the role for poly(ADP-ribose) polymerase activation in diabetic nephropathy, neuropathy and retinopathy.
[Back to top] Role of Oxidative and
Nitrosative Stress, Longevity Genes and Poly(ADPribose) Polymerase in Cardiovascular
Dysfunction Associated with Aging
Anna Csiszar, Pal Pacher, Gabor Kaley and Zoltan Ungvari
Epidemiological studies demonstrated that even in the absence of other risk factors (e.g. diabetes, hypertension, hypercholesterolemia), advanced age itself significantly increases cardiovascular morbidity. Although aging is inevitable, cardiovascular gerontologists recognize that a better understanding of the aging process in the not-so-distant future will lead to pharmacological interventions that considerably delay the functional decline of the cardiovascular system. Since the original publishing of the free radical theory of aging, an increased production of reactive oxygen species has been implicated both in the aging process and the development of age-related cardiovascular diseases. This review focuses on the role of oxidative and nitrosative stress in cardiovascular dysfunction in aging, downstream mechanisms including activation of NF-kB, and the role of poly(ADP-ribose)polymerase (PARP) and longevity genes that are linked to regulation of cellular redox status and oxidative stress resistance (p66shc, sirtuins, FOXO transcription factors).
[Back to top] Role of Nitrosative
Stress and Activation of Poly(ADP-ribose) Polymerase-1 in Cardiovascular
Failure Associated with Septic and Hemorrhagic Shock
Oleg V. Evgenov and Lucas Liaudet
Reactive oxygen and nitrogen species, particularly peroxynitrite, are potent inducers of tissue damage during systemic inflammatory response and circulatory shock. Recent evidence indicates that the toxicity of these species largely depends on their ability to trigger activation of the nuclear enzyme poly(adenosine 5’-diphosphate ribose) polymerase-1 (PARP-1). Following excessive activation, PARP-1 depletes the intracellular stores of its substrate, nicotinamide adenine dinucleotide, thus slowing glycolysis, generation of high energy phosphates, and mitochondrial electron transport. Consequently, the severe metabolic crisis induced by PARP-1 activation results in acute cell dysfunction and necrotic cell death. In addition, activation of PARP-1 plays an important role in the upregulation of inflammatory cascades via a functional association with mitogen-activated protein kinases and several transcription factors, such as nuclear factor kappa B, resulting in augmented expression of pro-inflammatory cytokines, chemokines, adhesion molecules, and enzymes. In severe sepsis and hemorrhage, PARP-1 activation has emerged as one of the central mechanisms of systemic inflammation, endothelial dysfunction, peripheral vascular failure, and reduction of cardiac contractility. Innovative therapeutic strategies based on the pharmacological inhibition of PARP-1 catalytic activity might provide benefits by preventing tissue injury, organ dysfunction, and lethality associated with these conditions.
[Back to top] Pharmacological Inhibition of
Poly(ADP-ribose) Polymerase in Cardiovascular Disorders: Future Directions
Csaba Szabo
Poly(ADP-ribose) polymerase (PARP) activation plays a role in the pathogenesis of various cardiovascular and inflammatory diseases. Reactive oxygen and nitrogen species induce DNA single strand breaks, which serve as obligatory triggers for the activation of PARP. Pharmacological inhibitors of PARP attenuate ischemic and inflammatory cell and organ injury, and this property of the PARP inhibitors can be exploited for the experimental therapy of disease. As several classes of PARP inhibitors move towards clinical development, or have already entered clinical trials, we expect that in the upcoming few years, clinical proof of PARP inhibitors’ therapeutic effect will be obtained in human disease. Acute, life-threatening cardiovascular diseases (myocardial infarction, cardiopulmonary bypass in high-risk patients, and other, severe forms of ischemia-reperfusion to other organs including stroke and thoracoabdominal aneurysm repair) represent some of the initial development indications for PARP inhibitors.