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.
Highlights
Based on a detailed profiling of the temporospatial expression pattern of Oncostatin M (OSM) and leukemia inhibitory factor (LIF) during myocardial healing in mice, we demonstrate for the first time that a short-term, post-infarction delivery of recombinant human-like OSM (hlOSM) was superior compared to administration of murine LIF (mLIF) or mOSM alone to improve cardiac architecture and contractility after myocardial infarction (MI)
By replacing the amino acid sequence of the murine AB loop by the corresponding human protein, we were able to create a human-like OSM mutant protein that is capable to signal via the oncostatin M receptor (OSMR) and leukemia inhibitory factor receptor (LIFR) in murine cells as reported previously [17] (Figure 1A,B)
RNA was isolated from murine cardiomyocytes stimulated with mLIF, mOSM and hlOSM for 24 h (Figure 2A)
Summary
The onset of myocardial infarction (MI) features a rapid but transient inflammatory response at sites of injury. Infiltrating immune cells and cardiac resident cells subsequently release a plethora of cytokines, whose task is to initiate, adjust and terminate cardiac repair events [1]. Insufficient and excessive expression of inflammatory cytokines are associated with impaired myocardial healing and progression to heart failure, respectively [2,3]. Cytokines have gained interest as potential targets for the treatment of MI. Inhibition strategies of individual cytokines as the prevailing therapeutic approach in clinical trials mostly produced disappointing and inconsistent results [4]
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