Dysregulation of catalase activity in newborn myocytes during hypoxia is mediated by c-Abl tyrosine kinase.
In the adult heart, catalase (CAT) activity increases appropriately with increasing levels of hydrogen peroxide, conferring cardioprotection. This mechanism is absent in the newborn for unknown reasons. In the present study, we examined how the posttranslational modification of CAT contributes to its activation during hypoxia/ischemia and the role of c-Abl tyrosine kinase in this process. Hypoxia studies were carried out using primary cardiomyocytes from adult (>8 weeks) and newborn rats. Following hypoxia, the ratio of phosphorylated to total CAT and c-Abl in isolated newborn rat myocytes did not increase and were significantly lower (1.3- and 4.2-fold, respectively; P < .05) than their adult counterparts. Similarly, there was a significant association (P < .0005) between c-Abl and CAT in adult cells following hypoxia (30.9 ± 8.2 to 70.7 ± 13.1 au) that was absent in newborn myocytes. Although ubiquitination of CAT was higher in newborns compared to adults following hypoxia, inhibition of this did not improve CAT activity. When a c-Abl activator (5-(1,3-diaryl-1H-pyrazol-4-yl)hydantoin [DPH], 200 µmol/L) was administered prior to hypoxia, not only CAT activity was significantly increased (P < .05) but also phosphorylation levels were also significantly improved (P < .01) in these newborn myocytes. Additionally, ischemia-reperfusion (IR) studies were performed using newborn (4-5 days) rabbit hearts perfused in a Langendorff method. The DPH given as an intracardiac injection into the right ventricle of newborn rabbit resulted in a significant improvement (P < .002) in the recovery of developed pressure after IR, a key indicator of cardiac function (from 74.6% ± 6.6% to 118.7% ± 10.9%). In addition, CAT activity was increased 3.92-fold (P < .02) in the same DPH-treated hearts. Addition of DPH to adult rabbits in contrast had no significant effect (from 71.3% ± 10.7% to 59.4% ± 12.1%). Therefore, in the newborn, decreased phosphorylation of CAT by c-Abl potentially mediates IR-induced dysfunction, and activation of c-Abl may be a strategy to prevent ischemic injury associated with surgical procedures.
Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA, USA Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
E Bernadette
EB
Cabigas
Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA, USA Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
Jie
J
Liu
Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA, USA Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
Archana V
AV
Boopathy
Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA, USA Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
Pao Lin
PL
Che
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA Emory+Children's Center for Cardiovascular Biology, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Brian H
BH
Crawford
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA Emory+Children's Center for Cardiovascular Biology, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Gitangali
G
Baroi
Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA, USA Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
Srishti
S
Bhutani
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA Emory+Children's Center for Cardiovascular Biology, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Ming
M
Shen
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA Emory+Children's Center for Cardiovascular Biology, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Mary B
MB
Wagner
Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Institute of Technology, Atlanta, GA, USA Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA Emory+Children's Center for Cardiovascular Biology, Children's Healthcare of Atlanta, Atlanta, GA, USA michael.davis@bme.emory.edu.
Michael E
ME
Davis
D000818:Animals; D000831:Animals, Newborn; D002374:Catalase / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D016313:Genes, abl / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000201:enzymology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D002374:Catalase; D011505:Protein-Tyrosine Kinases
catalase; hypoxia; ischemia–reperfusion; newborn