Poly(ADP-Ribose) Polymerase Is Activated in Subjects at Risk of Developing Type 2 Diabetes and Is Associated With Impaired Vascular Reactivity

Abstract

Background-We have previously shown that endothelial function is impaired not only in diabetes but also in subjects at risk of developing type 2 diabetes. We hypothesized that changes in the expression or activity of the endothelial isoform of nitric oxide synthase (eNOS), the receptor for advanced glycation end products (RAGE), and poly(ADP-ribose) polymerase (PARP) are related to this impairment. Methods and Results-We included a control group of 21 healthy subjects, a group of 22 healthy individuals with parental history of type 2 diabetes, a group of 23 subjects with impaired glucose tolerance, and a group of 21 type 2 diabetic patients. Two 2-mm forearm skin biopsies were taken from each participant and used for measurements. The percentage of PARP-positive endothelial nuclei was higher in the group with parental history of type 2 diabetes and diabetic patients compared with the controls (PϽ0.001). Immunoreactivity for nitrotyrosine (a marker of reactive nitrogen species) was higher in the diabetic group compared with all other groups (PϽ0.01). No differences in the expression of eNOS and RAGE were found among all 4 groups. The polymorphism of the eNOS gene was also studied and was not found to influence eNOS expression or microvascular functional measurements. Conclusions-PARP activation is present in healthy subjects at risk of developing diabetes as well as in established type 2 diabetic patients, and it is associated with impairments in the vascular reactivity in the skin microcirculation.

Characterization of the transcriptional machinery bound across the widely presumed type 2 diabetes causal variant, rs7903146, within TCF7L2

“…For example, PARP activation has been shown to be present in healthy subjects at risk of developing diabetes, as well as in established type 2 diabetics. 23 PARP-1 inhibitors have also been shown to alleviate symptoms of diabetic complications. [24][25][26] Furthermore, PARP-deficient mice are protected from streptozotocininduced diabetes.…”

The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

“…On the other hand, overactivation of PARP represents an important mechanism of tissue damage in various pathological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury (Zingarelli et al 1998), heart transplantation , heart failure (Pacher et al 2002b, c), stroke (Eliasson et al 1997), circulatory shock (Szabó et al 1997a, Oliver et al 1999, Jagtap et al 2002, Shimoda et al 2003, and autoimmune beta-cell destruction associated with diabetes mellitus (Burkart et al 1999, Pieper et al 1999. Activation of PARP and beneficial effects of various PARP inhibitors have been demonstrated in various forms of endothelial dysfunction such as the one associated with circulatory shock, hypertension, atherosclerosis, preeclampsia and aging (Szabó et al 1997, Hung et al 2002, Martinet et al 2002.…”

“…Activation of PARP and beneficial effects of various PARP inhibitors have been demonstrated in various forms of endothelial dysfunction such as the one associated with circulatory shock, hypertension, atherosclerosis, preeclampsia and aging (Szabó et al 1997, Hung et al 2002, Martinet et al 2002. Furthermore, recent data suggest that activation of PARP importantly contributes to the development of endothelial dysfunction in various experimental models of diabetes and also in humans (Garcia Soriano et al 2001, Soriano et al 2001a, Pacher et al 2002d, Szabó et al 2002b). In addition, it has recently been demonstrated that PARP activation plays a pathogenetic role in diabetic nephropathy, neuropathy and retinopathy , Minchenko et al 2003, Li et al 2004.…”

Nitrative stress and poly(ADP-ribose) polymerase activation in healthy and gestational diabetic pregnancies

“…Increased PARP activity can be measured in skin biopsies not only in patients with type 2 diabetes but also in healthy people with a parental history of type 2 diabetes (i.e. those with a higher risk of developing the disease) [30]. The prolonged PARP activation in GDM patients may be involved in the development of carbohydrate intolerance in later life or in the development of late cardiovascular complications.…”