title: Small proline-rich protein 1A is a gp130 pathway- and stress-inducible cardioprotective protein.
abstract: The interleukin-6 cytokines, acting via gp130 receptor pathways, play a pivotal role in the reduction of cardiac injury induced by mechanical stress or ischemia and in promoting subsequent adaptive remodeling of the heart. We have now identified the small proline-rich repeat proteins (SPRR) 1A and 2A as downstream targets of gp130 signaling that are strongly induced in cardiomyocytes responding to biomechanical/ischemic stress. Upregulation of SPRR1A and 2A was markedly reduced in the gp130 cardiomyocyte-restricted knockout mice. In cardiomyocytes, MEK1/2 inhibitors prevented SPRR1A upregulation by gp130 cytokines. Furthermore, binding of NF-IL6 (C/EBPbeta) and c-Jun to the SPRR1A promoter was observed after CT-1 stimulation. Histological analysis revealed that SPRR1A induction after mechanical stress of pressure overload was restricted to myocytes surrounding piecemeal necrotic lesions. A similar expression pattern was found in postinfarcted rat hearts. Both in vitro and in vivo ectopic overexpression of SPRR1A protected cardiomyocytes against ischemic injury. Thus, this study identifies SPRR1A as a novel stress-inducible downstream mediator of gp130 cytokines in cardiomyocytes and documents its cardioprotective effect against ischemic stress.
authors.affiliation: UCSD Institute of Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pradervand
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Olivier G
authors.initials: OG
authors.lastname: Muller
authors.forename: Harald
authors.initials: H
authors.lastname: Kjekshus
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Tara R
authors.initials: TR
authors.lastname: St Amand
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Yajima
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Matsumura
authors.forename: Hervé
authors.initials: H
authors.lastname: Duplain
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Iwatate
authors.forename: Sarah
authors.initials: S
authors.lastname: Woodard
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
authors.forename: John
authors.initials: J
authors.lastname: Ross
authors.forename: Dmitri
authors.initials: D
authors.lastname: Firsov
authors.forename: Bernard C
authors.initials: BC
authors.lastname: Rossier
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism*; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000378:metabolism*; D002470:Cell Survival; D055233:Cornified Envelope Proline-Rich Proteins; D003433:Crosses, Genetic; D050822:Cytokine Receptor gp130; D005456:Fluorescent Dyes; D005786:Gene Expression Regulation; D006834:Hydrazines; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D015428:Myocardial Reperfusion Injury; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C417561:Alexa 488 hydrazide; D015703:Antigens, CD; D002316:Cardiotonic Agents; D055233:Cornified Envelope Proline-Rich Proteins; D005456:Fluorescent Dyes; D006834:Hydrazines; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011506:Proteins; C524532:Sprr1a protein, mouse; D050822:Cytokine Receptor gp130