Abstract 18497: Serelaxin Renders Human Cardiomyocytes Resistant to Lethal Ischemia-Reperfusion Injury

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Background: Serelaxin, a synthetic analog of the vasoactive neurohormone relaxin-2, has been under investigation for the treatment of heart failure. However, emerging preclinical data suggest that serelaxin may have a largely unappreciated, acute cardioprotective effect: i.e., the agent may attenuate ischemia-reperfusion-induced cardiomyocyte death and reduce myocardial infarct size. Our aim in the current study was to establish whether this purported preclinical benefit of serelaxin is manifest in human cardiomyocytes.

Methods: To test this concept, cultured human iPSC-derived cardiomyocytes were subjected to 3 hours of simulated ischemia (achieved by oxygen and nutrient depletion) + reoxygenation. Serelaxin was administered at concentrations ranging from 0.1 to 100 ng/mL (including clinically relevant concentrations of 10 and 100 ng/mL), with treatment initiated: i) at one hour before the onset of simulated ischemia; or ii) in a delayed manner, during the ischemic insult. In each protocol, concurrent time-matched control cultures received an equivalent volume of vehicle (saline). Cell fate (expressed as % viable cells) following simulated ischemia-reoxygenation was quantified using the tetrazolium-based MTT assay.

Results: Pre-ischemic treatment with serelaxin evoked a significant and dose-dependent preservation of cardiomyocyte viability (Figure: **p<0.01 versus vehicle). Moreover, pretreatment with serelaxin was not a prerequisite for cardioprotection: at the highest dose of 100 ng/mL, efficacy was maintained when serelaxin was administered during simulated ischemia (data not shown).

Conclusion: These data provide novel evidence, obtained in human iPSC-derived cardiomyocytes, that clinically relevant concentrations of serelaxin may have a direct cardioprotective effect and render cardiomyocytes resistant to ischemia-reperfusion-induced death.

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