Sex-specific protection of endothelial function after ischemia/reperfusion injury in vascular grafts from mice by the senomorphic agent ruxolitinib

Lars Saemann (Halle (Saale))1, P. Naujoks (Halle (Saale))1, L. Hartrumpf (Halle (Saale))1, S. Pohl (Halle (Saale))1, A. Simm (Halle (Saale))1, G. Szabó (Halle (Saale))1

1Universitätsklinikum Halle (Saale) Universitätsklinik und Poliklinik für Herzchirurgie Halle (Saale), Deutschland


Purpose: Ischemia/Reperfusion (I/R)-induced endothelial dysfunction occurs after storage of vascular grafts. The release of cytokines partially drives I/R injury. The senomorphic JAK inhibitor ruxolitinib can block the release of cytokines. We investigated the effect of ruxolitinib on cytokine release and endothelial-dependent vasorelaxation in in-vitro I/R in vascular grafts from mice.

Methods: Aortic segments of C57BL/6J mice (N=12/group) were divided into three groups: Control, in vitro I/R (I/R group), and in vitro I/R with ruxolitinib during ischemic incubation (I/R+Ruxo group). We determined the cytokine expression. In organ bath chambers, we investigated the maximal vasoconstriction to phenylephrine (PEmax), maximal endothelial-dependent relaxation to acetylcholine (RmaxACh), and maximal endothelial-independent relaxation to sodium-nitroprusside (RmaxSNP).

Results: RmaxACh was decreased in I/R compared to Control (83.6±2.4 vs. 48.6±3.4%; p<0.05) and I/R+Ruxo (74.4±2.6 vs. 48.6±3.4%; p<0.05). RmaxSNP was comparable between all groups. IL-10 was detectable only in I/R+Ruxo. CXCL5, CCL2, CCL3, CCL8, CCL11, ICAM-1, IL-1α, IL-7, TNF-α, and G-CSF were decreased or not detectable in I/R+Ruxo. In I/R+Ruxo, ICAM-1 was reduced in rings only from male mice. Additionally, in this group, PEmax was significantly lower in male compared to female mice.

Conclusions: Treatment of vascular grafts from mice during in vitro ischemia with the senomorphic agent ruxolitinib reduces the cytokine release and protects the endothelium from I/R-mediated dysfunction in a sex-specific manner.

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