Improved preservation of hearts from old donors during static cold storage by the senomorphic agent ruxolitinib

Purpose Hearts from old donors are more likely to develop primary graft dysfunction, presumably due to reduced tolerance to ischemia/reperfusion injury, partially driven by proinflammatory cytokines. Accumulating senescent cells secrete the senescence-associated secretory phenotype (SASP), including proinflammatory cytokines, potentially intensifying IRI. Senomorphic agents block the SASP. We investigated the effect of the senomorphic agent ruxolitinib on the contractility of hearts from old donors. Methods We procured hearts from 24-month-old male and female C57BL6/J mice and preserved them by static cold storage (SCS) for 2 h using histidine-tryptophan-ketoglutarate (HTK) solution, without or with ruxolitinib (HTK + Ruxo), and measured contractility before and after SCS. In the Control group, hearts were not preserved by SCS ( N = 5 per Group and sex). We determined SASP-related cytokine release after SCS, JAK pathway, and nitrotyrosine levels. Results Especially in hearts from female mice (developed pressure, DP: 111 ± 17 vs. 44 ± 10%, p < 0.05) and (minimal slope of pressure decrement, dp/dt min : 103 ± 13 vs. 78 ± 8%), but also in hearts from male mice, the ventricular function (DP, 71 ± 9% vs. 47 ± 18%; dp/dt min , 87 ± 7% vs. 54 ± 10%) was higher in the HTK + Ruxo vs. the HTK group. IL-1 α , IL-7, and nitrotyrosine levels were lower in the HTK-Ruxo group, independent of sex, and TNF α was lower only in the hearts of female mice. The phosphorylation of JAK2 was increased in the hearts of male mice in the HTK group. Conclusion The senomorphic agent ruxolitinib improves contractility and modifies the SASP-related cytokine release during SCS of hearts from old donors in mice and is more effective in female hearts.