title: Loss of ErbB2-PI3K/Akt signaling prevents zinc pyrithione-induced cardioprotection during ischemia/reperfusion.
abstract: OBJECTIVE
  The purpose of this study was to determine if zinc homeostasis is affected during ischemia/reperfusion, if so, whether zinc pyrithione limits myocardial cell death and improves hemodynamics when administered as an adjunct to reperfusion and if ErbB receptor tyrosine kinases that are important for the long-term structural integrity of the heart are indispensable for reperfusion salvage.
  
  
  METHODS
  Isolated perfused rat hearts were subjected to 35min of global ischemia and reperfused for 120min to determine the relative intracellular zinc levels by TSQ staining. The hearts were reperfused in the presence of incremental concentrations of zinc pyrithione for the first 10min during reperfusion. Silencing or blockade of ErbB2 using a monoclonal antibody, ErbB2 kinase inhibition and PI3kinase inhibition was used to study their critical role in zinc pyrithione-induced cardioprotection.
  
  
  RESULTS
  We found that there was a profound decrease in intracellular zinc after ischemia/reperfusion resulting in increased apoptosis, caspase-3 activation, and infarct size. A dose-dependent reduction of infarct size with zinc pyrithione in the range of 5-20μmol/l (optimal protection was seen at 10μmol/l with infarct size of 16±2% vs. I/R vehicle, 33±2%, p<0.01). Increased TUNEL staining and caspase-3 activity observed after ischemia/reperfusion were attenuated by zinc pyrithione administration during the reperfusion. Moreover, this protection was sensitive to silencing and blockade of ErbB2, inhibition of ErbB2 kinase activity or PI3-kinase activity. Western blot analysis revealed that zinc pyrithione resulted in decreased caspase-3 activation, rapid stabilization of ErbB2/ErbB1 heterodimers, and increased activation of PI3K/Akt signaling cascade.
  
  
  CONCLUSIONS
  Zinc pyrithione attenuates lethal perfusion-induced injury in a manner that is reliant on ErbB2/PI3K/Akt activity.
authors.affiliation: Department of Biochemistry, Kakatiya University, Vidyaranyapuri, Warangal, Telangana, India.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Thokala
authors.affiliation: Institute of Genetics & Hospital for Genetic Diseases, Begumpet, Osmania University, Hyderabad, Telangana, India.
authors.forename: Santhipriya
authors.initials: S
authors.lastname: Inapurapu
authors.affiliation: Institute of Genetics & Hospital for Genetic Diseases, Begumpet, Osmania University, Hyderabad, Telangana, India.
authors.forename: Vijaya Lakshmi
authors.initials: VL
authors.lastname: Bodiga
authors.affiliation: Department of Biotechnology, KL University, Vaddeswaram, Guntur, Andhra Pradesh, India.
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Vemuri
authors.affiliation: Department of Biochemistry, Kakatiya University, Vidyaranyapuri, Warangal, Telangana, India. Electronic address: sbodiga@gmail.com.
authors.forename: Sreedhar
authors.initials: S
authors.lastname: Bodiga
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000187:drug effects; D020868:Gene Silencing; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000187:drug effects*; D009942:Organometallic Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D015032:Zinc / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D053148:Caspase 3; D009569:Nitric Oxide; D051058:Oncogene Protein v-akt; D009942:Organometallic Compounds; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D015032:Zinc; C483804:Erbb2 protein, rat; C505410:Casp3 protein, rat; C010423:pyrithione zinc
keywords: ErbB; Ischemia; Myocardium; Reperfusion; Zinc