Article: article from journal or magazin.
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.
Adenoviridae/genetics, Animals, Animals, Newborn, Antigens, CD/metabolism, Blotting, Western, Cardiotonic Agents/metabolism, Cell Survival, Cornified Envelope Proline-Rich Proteins, Crosses, Genetic, Cytokine Receptor gp130, Fluorescent Dyes, Gene Expression Regulation, Hydrazines, Interleukin-6/genetics, Interleukin-6/secretion, Membrane Glycoproteins/metabolism, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Myocardial Reperfusion Injury, Myocardium/cytology, Myocardium/metabolism, Myocytes, Cardiac/cytology, Myocytes, Cardiac/metabolism, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic, Proteins/metabolism, Signal Transduction
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