Anatomical and functional cardiac abnormalities in type I diabetes

Illán, Fátima; Valdés‐Chávarri, Mariano; Tebar, J. Cifuentes; Garcı́a, A.; Pascual, H; Soria, Federico; Hernández, Antonio; Vicente, T

doi:10.1007/bf00235521

Cited by 15 publications

(8 citation statements)

References 49 publications

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“…The presence of myocardial dysfunction independent of coronary artery disease in diabetes mellitus has been well documented in both humans and animals (Fein, 1990;Illan et al, 1992;Regan et al, 1994;Bell, 1995;FIG 8. Role of PARP in the development of endothelial cell dysfunction in diabetes mellitus.…”

Section: N Parp In the Pathogenesis Of Diabetic Cardiovascular Dysfumentioning

confidence: 99%

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

Virág

Szabó

2002

Pharmacological Reviews

1,282

1,246

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Poly(ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosylating) enzymes. PARP-1 is an abundant nuclear protein functioning as a DNA nick-sensor enzyme. Upon binding to DNA breaks, activated PARP cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors, and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. On the other hand, oxidative stress-induced overactivation of PARP consumes NAD(+) and consequently ATP, culminating in cell dysfunction or necrosis. This cellular suicide mechanism has been implicated in the pathomechanism of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis, and various other forms of inflammation. PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of nuclear factor kappa B-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Herein we review the double-edged sword roles of PARP in DNA damage signaling and cell death and summarize the underlying mechanisms of the anti-inflammatory effects of PARP inhibitors. Moreover, we discuss the potential use of PARP inhibitors as anticancer agents, radiosensitizers, and antiviral agents.

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Section: N Parp In the Pathogenesis Of Diabetic Cardiovascular Dysfumentioning

confidence: 99%

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

Virág

Szabó

2002

Pharmacological Reviews

1,282

1,246

View full text Add to dashboard Cite

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“…The mechanism of diastolic dysfunction remains unknown but it does not appear to be due to changes in blood pressure, microvascular complications or elevated circulating glycated hemoglobin levels [78][79][80][81][82]. There is circumstantial clinical and experimental evidence suggesting that increased sympathetic activity, activated cardiac renin-angiotensin system, myocardial ischemia/functional hypoxia, and elevated circulating levels of glucose result in oxidative and nitrosative stress in cardiovascular system of diabetic animals and humans.…”

Section: The Role Of Oxidative and Nitrosative Stress In The Pathogenmentioning

confidence: 99%

Role of Nitrosative Stress and Peroxynitrite in the Pathogenesis of Diabetic Complications. Emerging New Therapeutical Strategies

Pacher

Obrosova

Mabley

et al. 2005

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Macro-and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP.

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“…The presence of myocardial dysfunction independent of coronary artery disease in diabetes, known as "diabetic cardiomyopathy," has been well documented in both humans and animals (11)(12)(13)(14)(15). Diabetic cardiomyopathy is characterized by an early diastolic dysfunction and a late systolic one, with intracellular retention of calcium and sodium and loss of potassium.…”

mentioning

confidence: 99%

The Role of Poly(ADP-Ribose) Polymerase Activation in the Development of Myocardial and Endothelial Dysfunction in Diabetes

et al. 2002

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Patients with diabetes exhibit a high incidence of diabetic cardiomyopathy and vascular complications, which underlie the development of retinopathy, nephropathy, and neuropathy and increase the risk of hypertension, stroke, and myocardial infarction. There is emerging evidence that the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) importantly contributes to the development of endothelial dysfunction in a streptozotocin-induced model of diabetes. We investigated the role of PARP activation in the pathogenesis of cardiac dysfunction in streptozotocin-induced and genetic (nonobese diabetic) models of diabetes in rats and mice. Development of diabetes was accompanied by hyperglycemia, cardiac PARP activation, a selective loss of endothelium-dependent vasodilation in the thoracic aorta, and an early diastolic dysfunction of the heart. Treatment with a novel potent phenanthridinonebased PARP inhibitor, PJ34, starting 1 week after the onset of diabetes, restored normal vascular responsiveness and significantly improved cardiac dysfunction, despite the persistence of severe hyperglycemia. The beneficial effect of PARP inhibition persisted even after several weeks of discontinuation of the treatment. Thus, PARP activation plays a central role in the pathogenesis of diabetic cardiovascular (cardiac as well as endothelial) dysfunction. PARP inhibitors may exert beneficial effects against the development of cardiovascular complications in diabetes. Diabetes 51:514 -521, 2002 P oly(ADP ribose) polymerase (PARP), also known as poly(ADP ribose) synthetase (PARS), is an abundant nuclear enzyme of eukaryotic cells that participates in DNA repair in response to genotoxic stress. When activated by DNA single-strand breaks, PARP initiates an energy-consuming cycle by transferring ADP ribose units from NAD ϩ to nuclear proteins. This process results in rapid depletion of the intracellular NAD ϩ and ATP pools, slowing the rate of glycolysis and mitochondrial respiration, eventually leading to cellular dysfunction and death (1-7). Overactivation of PARP represents an important mechanism of tissue damage in various pathological conditions associated with oxidant stress, including myocardial reperfusion injury (4), stroke (3), shock (7,8), and autoimmune ␤-cell destruction (5,6). Recently, we reported that the activation of PARP importantly contributes to the development of endothelial dysfunction in a streptozotocin (STZ)-induced model of diabetes in mice (9,10).Cardiovascular complications are the most common cause of morbidity and mortality in diabetic patients. The presence of myocardial dysfunction independent of coronary artery disease in diabetes, known as "diabetic cardiomyopathy," has been well documented in both humans and animals (11-15). Diabetic cardiomyopathy is characterized by an early diastolic dysfunction and a late systolic one, with intracellular retention of calcium and sodium and loss of potassium. The mechanism of diastolic dysfunction remains unknown, but it does not appear to be due to cha...

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Anatomical and functional cardiac abnormalities in type I diabetes

Cited by 15 publications

References 49 publications

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

Role of Nitrosative Stress and Peroxynitrite in the Pathogenesis of Diabetic Complications. Emerging New Therapeutical Strategies

The Role of Poly(ADP-Ribose) Polymerase Activation in the Development of Myocardial and Endothelial Dysfunction in Diabetes

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