title: Protein kinase Calpha negatively regulates systolic and diastolic function in pathological hypertrophy.
abstract: The protein kinase C (PKC) family is implicated in cardiac hypertrophy, contractile failure, and beta-adrenergic receptor (betaAR) dysfunction. Herein, we describe the effects of gain- and loss-of-PKCalpha function using transgenic expression of conventional PKC isoform translocation modifiers. In contrast to previously studied PKC isoforms, activation of PKCalpha failed to induce cardiac hypertrophy, but instead caused betaAR insensitivity and ventricular dysfunction. PKCalpha inhibition had opposite effects. Because PKCalpha is upregulated in human and experimental cardiac hypertrophy and failure, its effects were also assessed in the context of the Galphaq overexpression model (in which PKCalpha is transcriptionally upregulated). Normalization (inhibition) of PKCalpha activity in Galpha(q) hearts improved systolic and diastolic function, whereas further activation of PKCalpha caused a lethal restrictive cardiomyopathy with marked interstitial fibrosis. These results define pathological roles for PKCalpha as a negative regulator of ventricular systolic and diastolic function.
authors: Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, Ohio 45267-0542, USA.
authors: Harvey S
authors: HS
authors: Hahn
authors: Yehia
authors: Y
authors: Marreez
authors: Amy
authors: A
authors: Odley
authors: Amber
authors: A
authors: Sterbling
authors: Martin G
authors: MG
authors: Yussman
authors: K Chad
authors: KC
authors: Hilty
authors: Ilona
authors: I
authors: Bodi
authors: Stephen B
authors: SB
authors: Liggett
authors: Arnold
authors: A
authors: Schwartz
authors: Gerald W
authors: GW
authors: Dorn
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D009202:Cardiomyopathies / Q000201:enzymology / Q000473:pathology; D002469:Cell Separation; D003971:Diastole; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D021381:Protein Transport / Q000235:genetics; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013599:Systole; D018754:Ventricular Dysfunction / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics
chemical_list: D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D010455:Peptides; D011943:Receptors, Adrenergic, beta; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D043802:GTP-Binding Protein alpha Subunits, Gq-G11