Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis.

摘要: Interleukin (IL) 35 is a novel immunosuppressive heterodimeric cytokine in IL-12 family. Whether and how IL-35 regulates ischemia-induced angiogenesis peripheral artery diseases are unrevealed. To fill this important knowledge gap, we used loss-of-function, gain-of-function, omics data analysis, RNA-Seq, vivo vitro experiments, have made the following significant findings: i) its receptor subunit IL-12RB2, but not IL-6ST, induced muscle after hindlimb ischemia (HLI); ii) HLI-induced improved Il12rb2-/- mice, ApoE-/-/Il12rb2-/- mice compared to WT ApoE-/- controls, respectively, where hyperlipidemia inhibits vitro; iii) injection as gain-of-function approach delays blood perfusion recovery at day 14 HLI; iv) spares regenerative late phase of HLI v) Transcriptome analysis endothelial cells (ECs) days post-HLI reveals disturbed extracellular matrix re-organization IL-35-injected mice; vi) downregulates three reactive oxygen species (ROS) promoters upregulates one ROS attenuator, which may functionally mediate upregulation anti-angiogenic proteins ECs; vii) human microvascular EC migration tube formation mainly through upregulating matrix-remodeling proteins. These findings provide insight on future therapeutic potential suppressing ischemia/inflammation-triggered inflammatory early sparing phase.