NDLI: Vincristine Attenuates N-methyl-N′-nitro-N-nitrosoguanidine-Induced Poly-(ADP) Ribose Polymerase Activity in Cardiomyocytes

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Vincristine Attenuates N-methyl-N′-nitro-N-nitrosoguanidine-Induced Poly-(ADP) Ribose Polymerase Activity in Cardiomyocytes

Content Provider	PubMed Central
Author	Zhang, Jianqing Chatterjee, Kanu Alano, Conrad C. Kalinowski, Mikaila A. Norman, Honbo Karliner, Joel S.
Abstract	The DNA-damaging agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) causes cardiomyocyte death as a result of energy loss from excessive activation of poly-(ADP) ribose polymerase-1 (PARP-1) resulting in depletion of its substrates nicotinamide adenine dinucleotide (NAD+) and ATP. Previously we showed that the chemotherapeutic agent vincristine (VCR) is cardioprotective. Here we tested the hypothesis that VCR inhibits MNNG-induced PARP activation. Adult mouse cardiomyocytes were incubated with 100 μmol/L MNNG with or without concurrent VCR (20 μmol/L) for 2 to 4 hours. Cardiomyocyte survival was measured using the trypan blue exclusion assay. Western blots were used to measure signaling responses. MNNG-induced cardiomyocyte damage was time- and concentration-dependent. MNNG activated PARP-1 and depleted NAD+ and ATP. VCR completely protected cardiomyocytes from MNNG-induced cell damage and maintained intracellular levels of NAD+ and ATP. VCR increased phosphorylation of the prosurvival signals Akt, GSK-3β, Erk1/2, and p70S6 kinase. VCR delayed PARP activation as evidenced by Western blot and by immunofluorescence staining of poly (ADP)-ribose, but without directly inhibiting PARP-1 itself. Known PARP-1 inhibitors also protected cardiomyocytes from MNNG-induced death. Repletion of ATP, NAD, pyruvate, and glutamine had effects similar to PARP-1 inhibitors. We conclude that VCR protects cardiomyocytes from MNNG toxicity by regulating PARP-1 activation, intracellular energy metabolism, and prosurvival signaling.
Related Links	http://dx.doi.org/10.1097/fjc.0b013e3181c87e6c
Ending Page	226
Page Count	8
Starting Page	219
File Format	PDF
ISSN	01602446
e-ISSN	15334023
Journal	Journal of cardiovascular pharmacology
Issue Number	3
Volume Number	55
Language	English
Publisher Date	2010-03-01
Access Restriction	Open
Subject Keyword	Pharmacology Cardiology and Cardiovascular Medicine Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Pharmacology Cardiology and Cardiovascular Medicine

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