Interleukin‐19 Can Simultaneously Reduce Atherosclerosis and Increase Perfusion in Hind Limb Ligated LDLr−/− Mice

Abstract

Peripheral arterial disease is often a co‐morbidity with hypercholesterolemia and atherosclerosis. We have previously characterized Interleukin‐19 (IL‐19) as an anti‐inflammatory, Th2 cytokine. Past studies in our lab have determined that IL‐19 can decrease atherosclerosis in LDLr−/− mice and increase angiogenesis in the hind limb ischemia (HLI) model, suggesting that IL‐19 has both anti‐atherosclerotic and pro‐angiogenic effects.ObjectiveThe purpose of this study was to determine whether IL‐19 can induce angiogenesis within the background of hyperlipidemia and atherosclerosis and potentially reduce atherosclerosis and induce angiogenesis simultaneously.Methods and ResultsWe utilized three different, yet complementary platforms to test this hypothesis. We fed LDLr−/− mice high fat diet (HFD) for 12 weeks, then performed HLI surgery and continued HFD and treatment with rIL‐19 (10ng/g/day) or PBS intraperitoneal (IP) injections for an additional 4 weeks. Doppler imaging revealed increased perfusion in mice treated with IL‐19 when compared to PBS controls. Additional en face evaluation of the aortic arches of these mice demonstrated a trend toward decreased plaque burden in the IL‐19 treated mice, though it was not statistically significant. These data suggest that IL‐19 is capable of promoting angiogenesis, even in a hyperlipidemic environment. We used this same experimental model, but instead treated LDLr−/− mice with IL‐19 (10ng/g/day) or PBS by daily IP injection throughout the initial 12 weeks of HFD, in addition to four weeks following HLI surgery. Doppler imaging demonstrated increased perfusion in IL‐19 treated mice when compared to PBS controls, and en face evaluation showed decreased plaque burden in the IL‐19 treated mice, supporting our hypothesis that IL‐19 is capable of simultaneously decreasing atherosclerosis and promoting angiogenesis in the background of hyperlipidemia. Finally, we hypothesized that lack of IL‐19 would both reduce perfusion and exacerbate atherosclerosis. We generated a double knockout mouse model (dKO) by crossing the LDLr−/− with an IL‐19−/− mouse. We placed dKO and LDLr−/− mice on HFD for 12 weeks, completed HLI and performed Doppler imaging for 4 weeks. Preliminary results suggest dKO mice demonstrate both decreased perfusion and increased plaque burden.ConclusionsThe current dogma referred to as the Janus phenomenon suggests that pro‐angiogenic cytokines are also pro‐atherosclerotic. Collectively, these data suggest IL‐19 is the only cytokine to date that challenges this theory, demonstrating both pro‐angiogenic and anti‐atherosclerotic effects.Support or Funding InformationThis work was supported by grants HL115575 and HL117724 from the National Heart Lung, and Blood Institute of the National Institutes of Health, and Grant 13GRNT1685003 from the American Heart Association to MVA.