title: UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy.
abstract: Hypertrophy increases the risk of heart failure and arrhythmia. Prevention or reversal of the maladaptive hypertrophic phenotype has thus been proposed to treat heart failure. Chronic β-adrenergic receptor (β-AR) stimulation induces cardiomyocyte hypertrophy by elevating 3',5'-cyclic adenosine monophosphate (cAMP) levels and activating downstream effectors such protein kinase A (PKA). Conversely, hydrolysis of cAMP by phosphodiesterases (PDEs) spatiotemporally restricts cAMP signaling. Here, we demonstrate that PDE4, but not PDE3, is critical in regulating cardiomyocyte hypertrophy, and may represent a potential target for preventing maladaptive hypertrophy. We identify a sequence within the upstream conserved region 1 of PDE4D, termed UCR1C, as a novel activator of PDE4 long isoforms. UCR1C activates PDE4 in complex with A-kinase anchoring protein (AKAP)-Lbc resulting in decreased PKA signaling facilitated by AKAP-Lbc. Expression of UCR1C in cardiomyocytes inhibits hypertrophy in response to chronic β-AR stimulation. This effect is partially due to inhibition of nuclear PKA activity, which decreases phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In conclusion, PDE4 activation by UCR1C attenuates cardiomyocyte hypertrophy by specifically inhibiting nuclear PKA activity.
authors: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, E403 MSB, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
authors: Li
authors: L
authors: Wang
authors: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, E403 MSB, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
authors: Brian T
authors: BT
authors: Burmeister
authors: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, E403 MSB, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
authors: Keven R
authors: KR
authors: Johnson
authors: Institute of Cardiovascular and Medical Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G128QQ, Scotland, United Kingdom.
authors: George S
authors: GS
authors: Baillie
authors: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, E403 MSB, 835 South Wolcott Avenue, Chicago, IL 60612, USA; University of Illinois Cancer Center, College of Medicine, University of Illinois at Chicago, E403 MSB, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
authors: Andrei V
authors: AV
authors: Karginov
authors: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, E403 MSB, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
authors: Randal A
authors: RA
authors: Skidgel
authors: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, E403 MSB, 835 South Wolcott Avenue, Chicago, IL 60612, USA; University of Illinois Cancer Center, College of Medicine, University of Illinois at Chicago, E403 MSB, 835 South Wolcott Avenue, Chicago, IL 60612, USA; Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, E403 MSB, 835 South Wolcott Avenue, Chicago, IL 60612, USA; Jessie Brown VA Medical Center, 820 S Damen Ave, Chicago, IL 60612, USA. Electronic address: obryanj@uic.edu.
authors: John P
authors: JP
authors: O'Bryan
authors: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, E403 MSB, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
authors: Graeme K
authors: GK
authors: Carnegie
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D054758:A Kinase Anchor Proteins; D010455:Peptides; D020033:Protein Isoforms; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: 3′,5′-cyclic monophosphate (cAMP); A-kinase anchoring protein (AKAP); Compartmentalized signaling; Phosphodiesterase 4 (PDE4) activation; cardiomyocyte hypertrophy; protein kinase A (PKA)