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.