S100A8/A9 aggravates post-ischemic heart failure through activation of RAGE-dependent NF-[kappa]B signaling

• Verfasst von: Volz, Hans Christian [VerfasserIn]
• Verfasst von: Laohachewin, Danai [VerfasserIn]
• Verfasst von: Seidel, Cathrin [VerfasserIn]
• Verfasst von: Lasitschka, Felix [VerfasserIn]
• Verfasst von: Keilbach, Kirsten [VerfasserIn]
• Verfasst von: Wienbrandt, Alexandra [VerfasserIn]
• Verfasst von: Andrassy, Joachim [VerfasserIn]
• Verfasst von: Bierhaus, Angelika [VerfasserIn]
• Verfasst von: Kaya, Ziya [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Verfasst von: Andrassy, Martin [VerfasserIn]
• Titel: S100A8/A9 aggravates post-ischemic heart failure through activation of RAGE-dependent NF-[kappa]B signaling
• Verf.angabe: H. Christian Volz, Danai Laohachewin, Cathrin Seidel, Felix Lasitschka, Kirsten Keilbach, Alexandra R. Wienbrandt, Joachim Andrassy, Angelika Bierhaus, Ziya Kaya, Hugo A. Katus, Martin Andrassy
• E-Jahr: 2012
• Jahr: 10 February 2012
• Fussnoten: Gesehen am 30.07.2018
• Titel Quelle: Enthalten in: Basic research in cardiology
• Ort Quelle: [Darmstadt u.a.] : Steinkopff, 1937
• Jahr Quelle: 2012
• Band/Heft Quelle: 107 (March 2012) Artikel-Nummer 107, 16 Seiten
• ISSN Quelle: 1435-1803
• DOI: doi:10.1007/s00395-012-0250-z
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1578034272

Abstract

The extracellular heterodimeric protein S100A8/A9 activates the innate immune system through activation of the receptor of advanced glycation end products (RAGE) and Toll-like receptors. As activation of RAGE has recently been associated with sustained myocardial inflammation and heart failure (HF) we studied the role of S100A8/A9 in the development of post-ischemic HF. Hypoxia led to sustained induction of S100A8/A9 accompanied by increased nuclear factor (NF-)κB binding activity and increased expression of pro-inflammatory cytokines in cardiac fibroblasts and macrophages. Knockdown of either S100A8/A9 or RAGE rescued the induction of pro-inflammatory cytokines and NF-κB activation after hypoxia. In a murine model of post-ischemic HF both cardiac RNA and protein levels of S100A8/A9 were elevated as soon as 30 min after hypoxia with sustained activation up to 28 days after ischemic injury. Treatment with recombinant S100A8/A9 resulted in reduced cardiac performance following ischemia/reperfusion. Chimera experiments after bone marrow transplantation demonstrated the importance of RAGE expression on immune cells for their recruitment to the injured myocardium aggravating post-ischemic heart failure. Signaling studies in isolated ventricles indicated that MAP kinases JNK, ERK1/2 as well as NF-κB mediate signals downstream of S100A8/A9-RAGE in post-ischemic heart failure. Interestingly, cardiac performance was not affected by administration of S100A8/A9 in RAGE−/−-mice, which demonstrated significantly improved cardiac recovery compared to WT-mice. Our study provides evidence that sustained activation of S100A8/A9 critically contributes to the development of post-ischemic HF driving the progressive course of HF through activation of RAGE.