title: Zinc pyrithione inhibits caspase-3 activity, promotes ErbB1-ErbB2 heterodimerization and suppresses ErbB2 downregulation in cardiomyocytes subjected to ischemia/reperfusion.
abstract: Heart tissue becomes zinc-depleted and the capacity to mobilize labile zinc is diminished, indicating zinc dyshomeostasis during ischemia/reperfusion (I/R). Apparently, zinc pyrithione restores the basal zinc levels during I/R and prevents apoptosis by activating phosphatidyl inositol-3-kinase/Akt and targeting mitochondrial permeability transition. Receptor tyrosine kinases of the ErbB family (ErbB1 to ErbB4) are cell surface proteins that can regulate cell growth, proliferation and survival. Previous studies have shown that zinc pyrithione-induced activation of PI3kinase/Akt requires ErbB2 expression. On the other hand, while I/R decreases ErbB2 levels causing cardiomyocyte dysfunction and cell death, zinc pyrithione restores ErbB2 levels and maintains cardiomyocyte function. H9c2 cells expressed all the four ErbBs, although the expression of ErbB1 and ErbB2 were higher compared to ErbB3 and ErbB4. Hypoxia/Reoxygenation (H/R) had opposing effects on the mRNA expression of ErbB1 and ErbB2. ErbB2 mRNA levels were enhanced, but corresponding ErbB2 protein levels decreased after reoxygenation. H/R induced the degradation of ErbB2 in caspase-3 dependent manner, with the formation of a 25kDa fragment. This fragment could be detected after H/R only upon treatment of the cells with a proteasomal inhibitor, ALLN, suggesting that caspase-mediated cleavage of 185kDa ErbB2 results in C-terminal cleavage and formation of 25kDa fragment, which is further degraded by proteasome. Heterodimerization and phosphorylation of ErbB2/ErbB1 which decreased upon reoxygenation, was promoted by zinc pyrithione. Zinc pyrithione effectively suppressed the caspase activation, decreased the proteolytic cleavage of ErbB2, enhanced the phosphorylation and activation of ErbB1-ErbB2 complexes and improved the cell survival after hypoxia/reoxygenation.
authors.affiliation: Department of Molecular Biology, Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, 500016 Telangana, India.
authors.forename: Vijaya Lakshmi
authors.initials: VL
authors.lastname: Bodiga
authors.affiliation: Department of Biochemistry, Kakatiya University, Warangal 506009, Telangana, India.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Thokala
authors.affiliation: Department of Biotechnology, KL University, Vaddeswaram, Guntur, 522502 Andhra Pradesh, India.
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Vemuri
authors.affiliation: Department of Biochemistry, Kakatiya University, Warangal 506009, Telangana, India. Electronic address: sbodiga@gmail.com.
authors.forename: Sreedhar
authors.initials: S
authors.lastname: Bodiga
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D015687:Cell Hypoxia; D002712:Chlorides / Q000494:pharmacology; D015536:Down-Regulation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000077341:Lapatinib; D007976:Leupeptins / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009942:Organometallic Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D061988:Proteasome Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization; D011725:Pyridines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013871:Thiones / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D017967:Zinc Compounds / Q000494:pharmacology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D052160:Benzothiazoles; D002316:Cardiotonic Agents; D053148:Caspase 3; D061945:Caspase Inhibitors; D002712:Chlorides; D066246:ErbB Receptors; D000077341:Lapatinib; D007976:Leupeptins; D009942:Organometallic Compounds; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D013871:Thiones; D020032:Tyrphostins; D017967:Zinc Compounds; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C098214:tyrphostin AG825; C063261:acetylleucyl-leucyl-norleucinal; C101044:RTKI cpd; C008704:pyrithione; C016837:zinc chloride; C483804:Erbb2 protein, rat; C505410:Casp3 protein, rat; C010423:pyrithione zinc
keywords: Apoptosis; Caspase-3; Hypoxia; Proteolysis; Reoxygenation; Zinc