title: Cardioprotection through a PKC-dependent decrease in myofilament ATPase.
abstract: Activation of myocardial kappa-opioid receptor-protein kinase C (PKC) pathways may improve postischemic contractile function through a myofilament reduction in ATP utilization. To test this, we first examined the effects of PKC inhibitors on kappa-opioid receptor-dependent cardioprotection. The kappa-opioid receptor agonist U50,488H (U50) increased postischemic left ventricular developed pressure and reduced postischemic end-diastolic pressure compared with controls. PKC inhibitors abolished the cardioprotective effects of U50. To determine whether kappa-opioid-PKC-dependent decreases in Ca2+-dependent actomyosin Mg2+-ATPase could account for cardioprotection, we subjected hearts to three separate actomyosin ATPase-lowering protocols. We observed that moderate decreases in myofibrillar ATPase were equally cardioprotective as kappa-opioid receptor stimulation. Immunoblot analysis and confocal microscopy revealed a kappa-opioid-induced increase in myofilament-associated PKC-epsilon, and myofibrillar Ca2+-independent PKC activity was increased after kappa-opioid stimulation. This PKC-myofilament association led to an increase in troponin I and C-protein phosphorylation. Thus we propose PKC-epsilon activation and translocation to the myofilaments causes a decrease in actomyosin ATPase, which contributes to the kappa-opioid receptor-dependent cardioprotective mechanism.
authors.affiliation: Department of Physiology, University of Tennessee-Memphis, 894 Union Avenue, Memphis, TN 38163, USA.
authors.forename: W Glen
authors.initials: WG
authors.lastname: Pyle
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Polly A
authors.initials: PA
authors.lastname: Hofmann
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D008841:Actin Cytoskeleton / Q000201:enzymology*; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D005260:Female; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; D002316:Cardiotonic Agents; D007527:Isoenzymes; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000255:Adenosine Triphosphate; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D000251:Adenosine Triphosphatases