Background: Beta-3 adrenergic receptor (β3AR) stimulation reduces myocardial ischemia/reperfusion injury (IRI) in vivo. The molecular mechanisms that regulate this cardioprotective therapy are a matter of intense research. The aim of this study was to assess the transcriptional reprogramming underpinning cardioprotection.
Methods and Results: HL-1 cardiomyocytes were subjected to 6 hours of hypoxia followed by 18h of reoxygenation (H/R) in the presence or absence of the beta-3 adrenergic receptor agonist BRL37344 (5μM). As expected, H/R caused cardiomyocyte death, which was significantly supressed by beta-3 agonist treatment. In order to uncover the molecular basis of cytoprotection we analysed gene expression profiles in HL-1 cells subjected to hypoxia (6h) and reoxygenation (1h, 6h). Immediate reoxygentation proufoundly altered the hypoxia gene expression signature at 1h but this effect was lost upon extended reoxygenation. BRL treatment was able to reverse transcriptomic alterations associated with increased cell death, by supressing the dysregulation of cell survival pathways (possibly implicating mTORC, EGF, eNOS, JAK/Stat, and IL-10 signalling.)
Conclusion: Beta-3-adrenergic stimulation induces an adaptive transcriptional reprogramming that preserves cell viability by converging a variety of cytoprotective pathways.