The Role of Poly(ADP-Ribose) Polymerase Activation in the Development of Myocardial and Endothelial Dysfunction in Diabetes
- Pal Pacher1,
- Lucas Liaudet2,
- Francisco Garcia Soriano2,
- Jon G. Mabley1,
- Éva Szabó1 and
- Csaba Szabó12
- 1Inotek Corporation, Beverly, Massachusetts
- 2Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, New Jersey
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 phenanthridinone-based 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.
Address correspondence and reprint requests to Csaba Szabó, Inotek Corporation, Suite 419E, 100 Cummings Center, Beverly, MA 01915. E-mail:.
Received for publication 17 July 2001 and accepted in revised form 1 November 2001.
P.P., J.G.M., E.S., and C.S. are employed by Inotek, which develops poly(ADP-ribose) polymerase inhibitors for the treatment of diabetes and other diseases. C.S. is a board member of and holds stock in Inotek.
ABC, avidin-biotin-peroxidase complex; DAB, diaminobenzidine; +dP/dt, systolic pressure increment; −dP/dt, systolic pressure decrement; PARP, poly(ADP-ribose) polymerase; STZ, streptozotocin.