title: Cardiotoxic and cardioprotective features of chronic β-adrenergic signaling.
abstract: BACKGROUND
  In the failing heart, persistent β-adrenergic receptor activation is thought to induce myocyte death by protein kinase A (PKA)-dependent and PKA-independent activation of calcium/calmodulin-dependent kinase II. β-adrenergic signaling pathways also are capable of activating cardioprotective mechanisms.
  
  
  OBJECTIVE
  This study used a novel PKA inhibitor peptide to inhibit PKA activity to test the hypothesis that β-adrenergic receptor signaling causes cell death through PKA-dependent pathways and cardioprotection through PKA-independent pathways.
  
  
  RESULTS
  In PKA inhibitor peptide transgenic mice, chronic isoproterenol failed to induce cardiac hypertrophy, fibrosis, and myocyte apoptosis, and decreased cardiac function. In cultured adult feline ventricular myocytes, PKA inhibition protected myocytes from death induced by β1-adrenergic receptor agonists by preventing cytosolic and sarcoplasmic reticulum Ca(2+) overload and calcium/calmodulin-dependent kinase II activation. PKA inhibition revealed a cardioprotective role of β-adrenergic signaling via cAMP/exchange protein directly activated by cAMP/Rap1/Rac/extracellular signal-regulated kinase pathway. Selective PKA inhibition causes protection in the heart after myocardial infarction that was superior to β-blocker therapy.
  
  
  CONCLUSIONS
  These results suggest that selective block of PKA could be a novel heart failure therapy.
authors.affiliation: Cardiovascular Research Center, Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.forename: Christopher
authors.initials: C
authors.lastname: Szeto
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Mingxin
authors.initials: M
authors.lastname: Tang
authors.forename: Jianguo
authors.initials: J
authors.lastname: Jin
authors.forename: Qin
authors.initials: Q
authors.lastname: Fu
authors.forename: Catherine
authors.initials: C
authors.lastname: Makarewich
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Ai
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Allen
authors.initials: A
authors.lastname: Tang
authors.forename: Jenny
authors.initials: J
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Xinyi Joy
authors.initials: XJ
authors.lastname: Ge
authors.forename: Satya P
authors.initials: SP
authors.lastname: Kunapuli
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zeng
authors.forename: Kevin Yang
authors.initials: KY
authors.lastname: Xiang
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D002415:Cats; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007545:Isoproterenol; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction; D013318:Stroke Volume; D013997:Time Factors; D014162:Transfection; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D047908:Intracellular Signaling Peptides and Proteins; C107593:Pkia protein, mouse; D011943:Receptors, Adrenergic, beta; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases; D020744:rac GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins; D007545:Isoproterenol; D002118:Calcium