Poly(ADP-ribose) polymerase contributes to the development of myocardial infarction in diabetic rats and regulates the nuclear translocation of apoptosis-inducing factor

Chun Yang Xiao, Min Chen, Zsuzsanna Zsengellér, Csaba Szabo

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)498-504
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume310
Issue number2
DOIs
StatePublished - Aug 2004
Externally publishedYes

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Apoptosis Inducing Factor
Poly(ADP-ribose) Polymerases
Myocardial Infarction
Myocardial Ischemia
Diabetes Mellitus
Myocardial Reperfusion Injury
Myocardial Reperfusion
Enzyme Activation
Mortality
Streptozocin
Reperfusion Injury
Oxidants
Muscle Cells
DNA Damage
Reperfusion
Ligation
Rodentia
Signal Transduction
Coronary Vessels
Myocardium

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Poly(ADP-ribose) polymerase contributes to the development of myocardial infarction in diabetic rats and regulates the nuclear translocation of apoptosis-inducing factor",
abstract = "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.",
author = "Xiao, {Chun Yang} and Min Chen and Zsuzsanna Zsengell{\'e}r and Csaba Szabo",
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AU - Zsengellér, Zsuzsanna

AU - Szabo, Csaba

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N2 - 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.

AB - 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.

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