In a variety of cell types (including vascular endothelial cells and vascular smooth muscle cells), exposure to cytotoxic oxidants such as peroxynitrite, results in cellular energetic failure. Upon DNA strand breakage, the nuclear enzyme poly (ADP) ribose synthetase (PARS) initiates an energy consuming, inefficient repair cycle, with transfer of the ADP ribosyl moiety of NAD to protein acceptors. The resultant depletion of dinucleotide pools is implicated in the process of cell death. In animal and cell culture models, a protective effect of PARS inhibition or lack of PARS gene has been demonstrated. Thus, the investigators propose to define the role of PARS in the process of development of endothelial injury in an in vitro model of diabetes-associated hyperglycemia.
Two specific aims are proposed: (1) to establish whether inhibition or genetic inactivation of PARS affects the development of endothelial dysfunction induced by high glucose conditions; and (2) to investigate the mechanism of high glucose-induced endothelial cell death and the role of PARS in the process.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL065145-01
Application #
6053423
Study Section
Special Emphasis Panel (ZRG1-MET (01))
Project Start
1999-09-30
Project End
2001-08-31
Budget Start
1999-09-30
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Inotek Pharmaceuticals Corporation
Department
Type
DUNS #
City
Beverly
State
MA
Country
United States
Zip Code
01915
Pacher, Pal; Liaudet, Lucas; Soriano, Francisco Garcia et al. (2002) The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes. Diabetes 51:514-21
Garcia Soriano F; Virag, L; Jagtap, P et al. (2001) Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med 7:108-13
Soriano, F G; Pacher, P; Mabley, J et al. (2001) Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ Res 89:684-91