Article
- The EMBO Journal (2004) 23, 4517 - 4525
- doi:10.1038/sj.emboj.7600454
Published online: 28 October 2004
Subject Category:
Small proline-rich protein 1A is a gp130 pathway- and stress-inducible cardioprotective protein
Sylvain Pradervand1, Hideo Yasukawa1, Olivier G Muller2, Harald Kjekshus1, Tomoyuki Nakamura1, Tara R St Amand1, Toshitaka Yajima1, Kiyoyuki Matsumura1, Hervé Duplain1, Mitsuo Iwatate1, Sarah Woodard1, Thierry Pedrazzini3, John Ross Jr1, Dmitri Firsov2, Bernard C Rossier2, Masahiko Hoshijima1 and Kenneth R Chien1
- UCSD Institute of Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
- Institute of Pharmacology and Toxicology, University of Lausanne, Switzerland
- Division of Hypertension, University of Lausanne, Switzerland
Correspondence to:
Kenneth R Chien, UCSD Institute of Molecular Medicine, University of California San Diego, La Jolla, CA 92093-0641, USA. Tel.: +1 858 534 6835; Fax: +1 858 534 8081; E-mail: kchien@ucsd.edu
Received 27 July 2004; Accepted 30 September 2004
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/EBP
) 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.
Keywords:
- gp130,
- IL-6 cytokines,
- myocardium,
- stress,
- SPRR1A
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