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

Abstract

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...

Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy

“…Recent findings, including those from our group, revealed the presence of diabetes-associated PARP activation in dorsal root ganglion neurons [25] and endothelial and Schwann cells of the peripheral nerve [5]. Growing evidence implicates PARP in the pathogenesis of chronic diabetic complications including endothelial and myocardial dysfunction [3,4], peripheral [5] and autonomic [33] neuropathy, and early retinopathy [16,32,34]. Direct evidence that PARP activation plays a role in diabetic nephropathy is still missing, although we have recently demonstrated that PARP activation is responsible for the overexpression of endothelin-1 and endothelin A and B receptors [10], the important players in diabetic kidney disease [35].…”

“…Poly(ADP-ribose) accumulation, the product of PARP activation, is found in all major tissue sites for diabetic complications, including in the vascular endothelium [3,4], myocardium [4], retina [16,32] and kidney [10] in rat and mouse models of STZdiabetes. Recent findings, including those from our group, revealed the presence of diabetes-associated PARP activation in dorsal root ganglion neurons [25] and endothelial and Schwann cells of the peripheral nerve [5].…”

“…cardiovascular and neurodegenerative diseases, cancer and inflammation [1]. Growing evidence indicates that PARP activation is an early pivotal mechanism in the pathogenesis of autoimmune diabetes mellitus [2] and chronic diabetic complications [3,4,5]. Activation has been documented in beta cells and tissue sites for diabetic complications in streptozotocin (STZ)-diabetic rats and mice [2,3,4,5], as well as in skin vessels of patients with diabetes mellitus [6], and it may lead to diabetic complications via several mechanisms.…”

“…Growing evidence indicates that PARP activation is an early pivotal mechanism in the pathogenesis of autoimmune diabetes mellitus [2] and chronic diabetic complications [3,4,5]. Activation has been documented in beta cells and tissue sites for diabetic complications in streptozotocin (STZ)-diabetic rats and mice [2,3,4,5], as well as in skin vessels of patients with diabetes mellitus [6], and it may lead to diabetic complications via several mechanisms. On the one hand, activation of PARP, which cleaves NAD to form nicotinamide and ADP-ribose residues, depletes NAD and ATP (or other high-energy phosphates), which are utilised for NAD regeneration from nicotinamide [1,3,5].…”

“…However, neither of these are orally active compounds, which makes them unsuitable for chronic experiments. Among other PARP inhibitors, the potent orally active PARP inhibitor PJ34 (the hydrochloride salt of N-(-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide [3,15]) has been that most extensively studied with regard to diabetic complications [3,4,7,15,16]. Long-term evaluation of the effect of PJ34 on diabetic retinopathy is in progress (T.S.…”