Abstract |
Poly(ADP-ribose) polymerase-1 (PARP-1), the most abundant member of the PARP family, is a nuclear enzyme that catalyzes ADP-ribose transfer from NAD+ to specific acceptor proteins in response to DNA damage. Excessive PARP-1 activation is an important cause of infarction and contractile dysfunction in heart tissue during interruptions of blood flow. The mechanisms by which PARP-1 inhibition and disruption dramatically improve metabolic recovery and reduce oxidative stress during cardiac reperfusion have not been fully explored. We developed a mouse heart experimental protocol to test the hypothesis that mitochondrial respiratory complex I is a downstream mediator of beneficial effects of PARP-1 inhibition or disruption. Pharmacological inhibition of PARP-1 activity produced no deterioration of hemodynamic function in C57BL/6 mouse hearts. Hearts from PARP-1 knockout mice also exhibited normal baseline contractility. Prolonged ischemia-reperfusion produced a selective defect in complex I function distal to the NADH dehydrogenase component. PARP-1 inhibition and PARP-1 gene disruption conferred equivalent protection against mitochondrial complex I injury and were strongly associated with improvement in myocardial energetics, contractility, and tissue viability. Interestingly, ischemic preconditioning abolished cardioprotection stimulated by PARP-1 gene disruption. Treatment with the antioxidant N-(2-mercaptopropionyl)-glycine or xanthine oxidase inhibitor allopurinol restored the function of preconditioned PARP-1 knockout hearts. This investigation establishes a strong association between PARP-1 hyperactivity and mitochondrial complex I dysfunction in cardiac myocytes. Our findings advance understanding of metabolic regulation in myocardium and identify potential therapeutic targets for prevention and treatment of ischemic heart disease.
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Authors | Hui-Zhong Zhou, Raymond A Swanson, Ursula Simonis, Xiaokui Ma, Gary Cecchini, Mary O Gray |
Journal | American journal of physiology. Heart and circulatory physiology
(Am J Physiol Heart Circ Physiol)
Vol. 291
Issue 2
Pg. H714-23
(Aug 2006)
ISSN: 0363-6135 [Print] United States |
PMID | 16582021
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Adenosine Diphosphate Ribose
- Parp1 protein, mouse
- Poly (ADP-Ribose) Polymerase-1
- Poly(ADP-ribose) Polymerases
- Creatine Kinase
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Topics |
- Adenosine Diphosphate Ribose
(metabolism)
- Animals
- Creatine Kinase
(metabolism)
- Electron Transport
(physiology)
- Enzyme Activation
- Hemodynamics
(physiology)
- In Vitro Techniques
- Ischemic Preconditioning, Myocardial
- Lipid Peroxidation
(physiology)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mitochondria, Heart
(enzymology)
- Myocardial Contraction
(physiology)
- Myocardial Infarction
(pathology)
- Myocardial Reperfusion
- Myocardium
(pathology)
- Organ Size
- Poly (ADP-Ribose) Polymerase-1
- Poly(ADP-ribose) Polymerases
(genetics, metabolism)
- Signal Transduction
(physiology)
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