This Article Full Text Full Text (PDF) All Versions of this Article: 106/21/2680    most recent 01.CIR.0000038365.78031.9Cv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Szabó, C. Articles by Veves, A. Search for Related Content PubMed PubMed Citation Articles by Szabó, C. Articles by Veves, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Diabetes Hazardous Substances DB L-TYROSINE Related Collections Type 2 diabetes Endothelium/vascular type/nitric oxide

(Circulation. 2002;106:2680.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

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

Csaba Szabó, MD, PhD; Anne Zanchi, MD; Katalin Komjáti, MD, PhD; Pál Pacher, MD, PhD; Andrzej S. Krolewski, MD; William C. Quist, MD; Frank W. LoGerfo, MD; Edward S. Horton, MD; Aristidis Veves, MD

From the Microcirculation Laboratory (A.V.), Division of Vascular Surgery (W.C.Q., F.W.L.), Beth Israel Deaconess Medical Center, Joslin Diabetes Center (A.Z., A.S.K., E.S.H.), Harvard Medical School, Boston, Mass; Institute of Human Physiology and Clinical Experimental Research (C.S., K.K.), Semmelweis University, Budapest, Hungary; and Inotek Pharmaceuticals Corporation (C.S., K.K., P.P.), Beverly, Mass.

Correspondence to Aristidis Veves, MD, Microcirculation Lab, Palmer 317, Beth Israel Deaconess Medical Center, West Campus, One Deaconess Road, Boston, MA 02215. E-mail aveves{at}caregroup.harvard.edu

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 (P<0.001). Immunoreactivity for nitrotyrosine (a marker of reactive nitrogen species) was higher in the diabetic group compared with all other groups (P<0.01). 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.

Key Words: diabetes mellitus • endothelium • acetylcholine • microcirculation

This article has been cited by other articles:

				P. Pacher and C. Szabo Role of the Peroxynitrite-Poly(ADP-Ribose) Polymerase Pathway in Human Disease Am. J. Pathol., July 1, 2008; 173(1): 2 - 13. [Abstract] [Full Text] [PDF]

				Y.-J. Chen and J. Quilley Fenofibrate Treatment of Diabetic Rats Reduces Nitrosative Stress, Renal Cyclooxygenase-2 Expression, and Enhanced Renal Prostaglandin Release J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 658 - 663. [Abstract] [Full Text] [PDF]

				S. Beneke and A. Burkle Poly(ADP-ribosyl)ation in mammalian ageing Nucleic Acids Res., December 3, 2007; 35(22): 7456 - 7465. [Abstract] [Full Text] [PDF]

				I. G. Obrosova, V. R. Drel, C. L. Oltman, N. Mashtalir, J. Tibrewala, J. T. Groves, and M. A. Yorek Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1645 - E1655. [Abstract] [Full Text] [PDF]

				I. G. Obrosova, O. Ilnytska, V. V. Lyzogubov, I. A. Pavlov, N. Mashtalir, J. L. Nadler, and V. R. Drel High-Fat Diet Induced Neuropathy of Pre-Diabetes and Obesity: Effects of "Healthy" Diet and Aldose Reductase Inhibition Diabetes, October 1, 2007; 56(10): 2598 - 2608. [Abstract] [Full Text] [PDF]

				M. Rajesh, P. Mukhopadhyay, S. Batkai, G. Hasko, L. Liaudet, V. R. Drel, I. G. Obrosova, and P. Pacher Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H610 - H619. [Abstract] [Full Text] [PDF]

				K. Oumouna-Benachour, C. P. Hans, Y. Suzuki, A. Naura, R. Datta, S. Belmadani, K. Fallon, C. Woods, and A. H. Boulares Poly(ADP-Ribose) Polymerase Inhibition Reduces Atherosclerotic Plaque Size and Promotes Factors of Plaque Stability in Apolipoprotein E-Deficient Mice: Effects on Macrophage Recruitment, Nuclear Factor-{kappa}B Nuclear Translocation, and Foam Cell Death Circulation, May 8, 2007; 115(18): 2442 - 2450. [Abstract] [Full Text] [PDF]

				C. Szabo, A. Biser, R. Benko, E. Bottinger, and K. Susztak Poly(ADP-Ribose) Polymerase Inhibitors Ameliorate Nephropathy of Type 2 Diabetic Leprdb/db Mice Diabetes, November 1, 2006; 55(11): 3004 - 3012. [Abstract] [Full Text] [PDF]

				J. C. Schramm, T. Dinh, and A. Veves Microvascular changes in the diabetic foot. International Journal of Lower Extremity Wounds, September 1, 2006; 5(3): 149 - 159. [Abstract] [PDF]

				P. Pacher, A. Nivorozhkin, and C. Szabo Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol. Rev., March 1, 2006; 58(1): 87 - 114. [Abstract] [Full Text] [PDF]

				M. Ayaz and B. Turan Selenium prevents diabetes-induced alterations in [Zn2+]i and metallothionein level of rat heart via restoration of cell redox cycle Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1071 - H1080. [Abstract] [Full Text] [PDF]

				T. L. Dinh and A. Veves A Review of the Mechanisms Implicated in the Pathogenesis of the Diabetic Foot International Journal of Lower Extremity Wounds, September 1, 2005; 4(3): 154 - 159. [Abstract] [PDF]

				E. B. Okon, A. W.Y. Chung, P. Rauniyar, E. Padilla, T. Tejerina, B. M. McManus, H. Luo, and C. van Breemen Compromised Arterial Function in Human Type 2 Diabetic Patients Diabetes, August 1, 2005; 54(8): 2415 - 2423. [Abstract] [Full Text] [PDF]

				T. B. Andrasi, A. Blazovics, G. Szabo, C. F. Vahl, and S. Hagl Poly(ADP-ribose) polymerase inhibitor PJ-34 reduces mesenteric vascular injury induced by experimental cardiopulmonary bypass with cardiac arrest Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2972 - H2978. [Abstract] [Full Text] [PDF]

				M. Fujimoto, N. Shimizu, K. Kunii, J.A. J. Martyn, K. Ueki, and M. Kaneki A Role for iNOS in Fasting Hyperglycemia and Impaired Insulin Signaling in the Liver of Obese Diabetic Mice Diabetes, May 1, 2005; 54(5): 1340 - 1348. [Abstract] [Full Text] [PDF]

				F. Li, V. R. Drel, C. Szabo, M. J. Stevens, and I. G. Obrosova Low-Dose Poly(ADP-Ribose) Polymerase Inhibitor-Containing Combination Therapies Reverse Early Peripheral Diabetic Neuropathy Diabetes, May 1, 2005; 54(5): 1514 - 1522. [Abstract] [Full Text] [PDF]

				C. Rask-Madsen and G. L. King Proatherosclerotic Mechanisms Involving Protein Kinase C in Diabetes and Insulin Resistance Arterioscler. Thromb. Vasc. Biol., March 1, 2005; 25(3): 487 - 496. [Abstract] [Full Text] [PDF]

				I. G. Obrosova, P. Pacher, C. Szabo, Z. Zsengeller, H. Hirooka, M. J. Stevens, and M. A. Yorek Aldose Reductase Inhibition Counteracts Oxidative-Nitrosative Stress and Poly(ADP-Ribose) Polymerase Activation in Tissue Sites for Diabetes Complications Diabetes, January 1, 2005; 54(1): 234 - 242. [Abstract] [Full Text] [PDF]

				C.-Y. Xiao, M. Chen, Z. Zsengeller, and C. Szabo Poly(ADP-Ribose) Polymerase Contributes to the Development of Myocardial Infarction in Diabetic Rats and Regulates the Nuclear Translocation of Apoptosis-Inducing Factor J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 498 - 504. [Abstract] [Full Text] [PDF]

				T. L. Dinh and A. Veves Microcirculation in the Diabetic Foot: An Update International Journal of Lower Extremity Wounds, June 1, 2004; 3(2): 60 - 61. [PDF]

				I. G. Obrosova, F. Li, O. I. Abatan, M. A. Forsell, K. Komjati, P. Pacher, C. Szabo, and M. J. Stevens Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy Diabetes, March 1, 2004; 53(3): 711 - 720. [Abstract] [Full Text] [PDF]

				G. Szabo, L. Liaudet, S. Hagl, and C. Szabo Poly(ADP-ribose) polymerase activation in the reperfused myocardium Cardiovasc Res, February 15, 2004; 61(3): 471 - 480. [Abstract] [Full Text] [PDF]

				A. Flyvbjerg, L. Denner, B. F. Schrijvers, R. G. Tilton, T. H. Mogensen, S. R. Paludan, and R. Rasch Long-Term Renal Effects of a Neutralizing RAGE Antibody in Obese Type 2 Diabetic Mice Diabetes, January 1, 2004; 53(1): 166 - 172. [Abstract] [Full Text] [PDF]

				P. Pacher, L. Liaudet, P. Bai, J. G. Mabley, P. M. Kaminski, L. Virag, A. Deb, E. Szabo, Z. Ungvari, M. S. Wolin, et al. Potent Metalloporphyrin Peroxynitrite Decomposition Catalyst Protects Against the Development of Doxorubicin-Induced Cardiac Dysfunction Circulation, February 18, 2003; 107(6): 896 - 904. [Abstract] [Full Text] [PDF]