The Effects of Interleukin‐1 Receptor Antagonism on Micro‐ and Macrovascular Function in Young and Old Fischer‐344 Rats

Abstract

BACKGROUND Interleukin‐1 (IL‐1) is a pro‐inflammatory cytokine that plays a role in systemic and local inflammatory responses, inhibiting vascular contractility and inducing vascular dysfunction. Interleukin‐1 receptor antagonists (IL‐1RA) block IL‐1 signaling by binding to the IL‐1 receptor. Thus, IL‐1RA may have protective effects on vascular function during bone healing. We sought to determine the influence of IL‐1RA on vasodilator capacity of the femoral principal nutrient artery (i.e., PNA) following a bone defect. Additionally, we sought to determine the influence of IL‐1RA administration on macrovascular function (i.e., aortic stiffness). METHODS Young (6 months) and old (24 months) male Fischer‐344 rats were randomly assigned to 1) young control (YC, n=7–8), young interleukin‐1 receptor antagonism (Y_IL‐1RA, n=5–7), old control (OC, n=5–6), and old interleukin‐1 receptor antagonism (O_IL‐1RA, n=5–10). Under anesthesia (2.0% isoflurane to O2 balance), rats underwent surgery to create a small bone defect in the right femur. During recovery, the control and IL‐1RA groups received PBS (100 μl/day, i.p.) or IL‐1RA (3 μg/kg, i.p.), respectively, 3 days/week for 3 weeks. To assess arterial stiffness in the aorta, pulse wave velocity (PWV; cm/sec) was measured prior to the surgery and before sacrifice. At sacrifice, right femoral PNAs were isolated and cannulated to assess endothelium‐dependent (acetylcholine [ACh]: 10−9 – 10−4 M) and endothelium‐independent (DEA NONOate [DEA]: 10−10 – 10−4 M) vasodilation. A One‐Way ANOVA and Repeated Measures ANOVAs were performed. Alpha was set a priori at p<0.05 and tendencies (p<0.10) are reported. RESULTS Body mass was higher (p<0.05) in the old (OC, 401±15 g and O_IL‐1RA, 410±10 g) vs. young (YC, 351±6 g and Y_IL‐1RA, 354±9 g) rats, but did not differ between the age‐matched groups. The maximal diameters of the PNA did not differ among groups (YC, 209±17 μm; Y_IL‐1RA, 209±15 μm; OC, 212±8 μm; O_IL‐1RA, 238±11 μm). IL‐1RA administration had no effect on endothelium‐dependent vasodilation of the femoral PNA, however, there was a tendency (p=0.056) for reduction in O_IL‐1RA vs. YC. Endothelium‐independent vasodilation was augmented (p<0.05) in OC vs. all other groups and was impaired (p<0.05) in O_IL‐1RA vs. OC. PWV was higher (p<0.05) in the old (OC, 478±10 cm/sec and O_IL‐1RA, 452±8 cm/sec) vs. young (YC, 396±10 cm/sec and Y_IL‐1RA, 369±10 cm/sec) groups, indicating greater aortic stiffness. In addition, there were tendencies for reduced aortic stiffness by 6.8% and 5.5% in Y_IL‐1RA (p=0.061) and O_IL‐1RA (p=0.056), respectively, vs. their age‐matched controls. CONCLUSIONS 1) IL‐1RA treatment reduced endothelium‐independent vasodilation of the femoral PNA (i.e., the microvasculature) in old animals. 2) Aortic stiffness was augmented as a function of advanced age. 3) 3‐weeks of IL‐1RA treatment tended to reduce stiffness in the macrovasculature of both young and old rats. Support or Funding Information Grant Support: American Heart Association: 16IRG27550003