Concomitant Activation of OSM and LIF Receptor by a Dual-Specific hlOSM Variant Confers Cardioprotection after Myocardial Infarction in Mice.

Abstract

Oncostatin M (OSM) and leukemia inhibitory factor (LIF) signaling protects the heart after myocardial infarction (MI). In mice, oncostatin M receptor (OSMR) and leukemia inhibitory factor receptor (LIFR) are selectively activated by the respective cognate ligands while OSM activates both the OSMR and LIFR in humans, which prevents efficient translation of mouse data into potential clinical applications. We used an engineered human-like OSM (hlOSM) protein, capable to signal via both OSMR and LIFR, to evaluate beneficial effects on cardiomyocytes and hearts after MI in comparison to selective stimulation of either LIFR or OSMR. Cell viability assays, transcriptome and immunoblot analysis revealed increased survival of hypoxic cardiomyocytes by mLIF, mOSM and hlOSM stimulation, associated with increased activation of STAT3. Kinetic expression profiling of infarcted hearts further specified a transient increase of OSM and LIF during the early inflammatory phase of cardiac remodeling. A post-infarction delivery of hlOSM but not mOSM or mLIF within this time period combined with cardiac magnetic resonance imaging-based strain analysis uncovered a global cardioprotective effect on infarcted hearts. Our data conclusively suggest that a simultaneous and rapid activation of OSMR and LIFR after MI offers a therapeutic opportunity to preserve functional and structural integrity of the infarcted heart.

• Authors: Holger Lörchner, Juan M Adrian-Segarra, Christian Waechter, Roxanne Wagner, Maria Elisa Góes, Nathalie Brachmann, Krishnamoorthy Sreenivasan, Astrid Wietelmann, Stefan Günther, Nicolas Doll, Thomas Braun, Jochen Pöling
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 1 (Dec 29 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35008777 (Publication Type: Journal Article)

Chemical References

• Cardiotonic Agents
• Leukemia Inhibitory Factor
• Proto-Oncogene Proteins c-myc
• Receptors, OSM-LIF
• Receptors, Oncostatin M
• STAT3 Transcription Factor
• STAT5 Transcription Factor
• Oncostatin M

Topics

• Animals
• Cardiotonic Agents (metabolism)
• Cell Hypoxia (genetics)
• Cell Survival
• Cells, Cultured
• Humans
• Kinetics
• Leukemia Inhibitory Factor (metabolism)
• Mice
• Myocardial Contraction
• Myocardial Infarction (genetics, prevention & control)
• Myocytes, Cardiac (metabolism)
• Oncostatin M (metabolism)
• Protein Engineering
• Proto-Oncogene Proteins c-myc (metabolism)
• Receptors, OSM-LIF (metabolism)
• Receptors, Oncostatin M (metabolism)
• STAT3 Transcription Factor (metabolism)
• STAT5 Transcription Factor (metabolism)
• Signal Transduction
• Species Specificity
• Transcriptome (genetics)