Small proline-rich protein 1A is a gp130 pathway- and stress-inducible cardioprotective protein.
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.
Pradervand
Sylvain
S
UCSD Institute of Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Yasukawa
Hideo
H
Muller
Olivier G
OG
Kjekshus
Harald
H
Nakamura
Tomoyuki
T
St Amand
Tara R
TR
Yajima
Toshitaka
T
Matsumura
Kiyoyuki
K
Duplain
Hervé
H
Iwatate
Mitsuo
M
Woodard
Sarah
S
Pedrazzini
Thierry
T
Ross
John
J
Firsov
Dmitri
D
Rossier
Bernard C
BC
Hoshijima
Masahiko
M
Chien
Kenneth R
KR
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
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