Ruxolitinib preserves endothelial function in middle-aged and old mice after ischemia/reperfusion injury

Ischemia/Reperfusion (I/R) and the increasing age of patients are coexisting challenges in today's cardiovascular medicine. Vascular I/R leads to endothelial dysfunction and is partially driven by inflammation. With increasing age, a profile of biomolecules known as the senescence-associated secretory phenotype (SASP) also increases. The SASP correlates with decreased resilience and intrinsic capacity to withstand various stressors and contains pro-inflammatory cytokines, likely fueling I/R injury. Senomorphics block SASP secretion. We investigated the effect of ruxolitinib on endothelial function after vascular I/R injury in middle-aged and old mice.

Aortic rings of 11-13 and 23-25 months old C57BL/6 J mice were divided into three groups: Control (12 mo: n = 9; 24 mo: n = 10), ischemia/reperfusion (I/R group; 12 mo: n = 9; 24 mo: n = 11), and I/R with ruxolitinib (I/R + Ruxo; 12 mo: n = 13; 24 mo: n = 15). The aortic rings were stored in de-aired saline solution for 24 h without (I/R) or with ruxolitinib (I/R + Rux). Afterward, they were mounted in organ bath chambers. The reperfusion injury was induced by 200 μM sodium hypochlorite. In the Control group, no ischemia or sodium hypochlorite was performed. We investigated the vasomotor function using potassium chloride (KCl), phenylephrine (PE), acetylcholine (ACh), and sodium nitroprusside (SNP).

The contraction to PE in % of KCl was higher in the I/R group (12 mo: 80 ± 10%; 24 mo: 94 ± 15%) compared to the control (12 mo: 51 ± 8%; 24 mo: 63 ± 13%) and lower in the I/R + Ruxo group (12 mo: 60 ± 9%; 24 mo: 70 ± 10%) compared to the I/R group, in both age populations. The maximal endothelial-dependent relaxation to ACh was substantially decreased in the I/R group (12 mo: 34 ± 6%; 24 mo: 34 ± 7%) compared to control (12 mo: 75 ± 5%; 24 mo: 88 ± 9%) and higher in the I/R + Ruxo group (12 mo: 59 ± 21%; 24 mo: 61 ± 12%) compared to I/R in both age populations. The endothelial-independent relaxation to SNP was comparable between all groups. The concentration of interleukin (IL)-1α, IL-7, IL-10, IL-13, and tumor necrosis factor-α was higher in the I/R + Ruxo group, only in 24-month-old mice. CC chemokine ligand (CCL)11, intercellular cell adhesion molecule-1, CCL8, RANTES, and C-X-C motif chemokine ligand 5 were comparable between I/R and I/R + Ruxo in 12- and 24-mo mice.

Treatment of the aorta with the senomorphic agent ruxolitinib during ischemic storage protects the endothelial-dependent vasomotor function of the aorta in both age groups.