Poly(ADP-ribose) polymerase-1 hyperactivation and impairment of mitochondrial respiratory chain complex I function in reperfused mouse hearts.

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.

• 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.)

Chemical References

• Adenosine Diphosphate Ribose
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Creatine Kinase

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)