Document Detail


Poly(ADP-ribose) polymerase contributes to the development of myocardial infarction in diabetic rats and regulates the nuclear translocation of apoptosis-inducing factor.
MedLine Citation:
PMID:  15054118     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 by oxidant-mediated DNA damage is an important pathway of cell dysfunction and tissue injury during myocardial infarction. Because diabetes mellitus can substantially alter cellular signal transduction pathways, we have now investigated whether the PARP pathway also contributes to myocardial ischemia/reperfusion (MI/R) injury in diabetes mellitus in rodents. Myocardial ischemia/reperfusion in control and streptozotocin-diabetic rats was induced by transient ligation of the left anterior descending coronary artery. PARP activation was inhibited by the isoindolinone derivative PARP inhibitor INO-1001. In diabetic rats, a more pronounced degree of myocardial contractile dysfunction developed, which also was associated with a larger infarct size, and significant mortality compared with nondiabetic rats. Inhibition of PARP provided a similar degree of myocardial protective effect in diabetic and nondiabetic animals and reduced infarct size and improved myocardial contractility. In diabetic rats, PARP inhibition reduced mortality during the reperfusion phase. There was marked activation of PARP in the ischemic/reperfused myocardium, which was blocked by INO-1001. In addition, there was a significant degree of mitochondrial-to-nuclear translocation of the cell death effector apoptosis-inducing factor (AIF) in myocardial infarction, which was blocked by pharmacological inhibition of PARP. The role of PARP in regulating AIF translocation in myocytes also was confirmed in an isolated perfused heart preparation. Overall, the current results demonstrate the importance of the PARP pathway in diabetic rats subjected to myocardial infarction and demonstrate the role of PARP in regulating AIF translocation in MI/R.
Authors:
Chun-Yang Xiao; Min Chen; Zsuzsanna Zsengellér; Csaba Szabó
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2004-03-30
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  310     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2004 Aug 
Date Detail:
Created Date:  2004-07-19     Completed Date:  2005-03-28     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  498-504     Citation Subset:  IM    
Affiliation:
Inotek Pharmaceuticals Corporation, Suite 419E, 100 Cummings Center, Beverly, MA 01915, USA. szabocsaba@aol.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis Inducing Factor
Cell Nucleus / drug effects,  metabolism
Diabetes Mellitus, Experimental / genetics,  metabolism*
Enzyme Activation / drug effects,  physiology
Flavoproteins / genetics,  metabolism*
Indoles / pharmacology
Male
Membrane Proteins / genetics,  metabolism*
Myocardial Infarction / genetics,  metabolism*
Poly(ADP-ribose) Polymerases / antagonists & inhibitors,  physiology*
Rats
Rats, Wistar
Grant Support
ID/Acronym/Agency:
R01 GM 60915/GM/NIGMS NIH HHS; R01 HL/DK 71246-01/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Inducing Factor; 0/Flavoproteins; 0/INO 1001; 0/Indoles; 0/Membrane Proteins; 0/Pdcd8 protein, rat; EC 2.4.2.30/Poly(ADP-ribose) Polymerases

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