Heme Oxygenase-1 in Macrophages Impairs the Perfusion Recovery After Hindlimb Ischemia by Suppressing Autolysosome-Dependent Degradation of NLRP3

Objective: Macrophage-mediated inflammatory response is closely associated with the neovascularization process following hindlimb ischemia. We previously demonstrated that HO-1 (heme oxygenase-1) in macrophages evoked proinflammatory reactions and tissue damage. Here, we evaluated role played by macrophage-derived elucidated its underlying molecular mechanisms perfusion recovery after Approach Results: found significant upregulation of mouse ischemic muscles ischemia surgery most this expression occurring infiltrated macrophages. Myeloid conditional HO-1-deficient mice exhibited higher recovery, evidenced restored blood flow, motor function attenuated damage as well increased capillary density gastrocnemius ischemia, relative to littermate controls. This protective effect was accompanied reduced NLRP3 (Nod-like receptor family pyrin domain containing 3) inflammasome activation without alteration macrophage infiltration polarization. Moreover, suppressing inhibitor MCC950 improved flow wild-type compared untreated mice. Mechanistically, abolished TNF (tumor necrosis factor)-α-induced protein rather than mRNA bone marrow–derived macrophages, indicating mediated post-transcriptional regulation NLRP3. Furthermore, inhibition promoted autolysosome-dependent degradation Matrigel tube formation assay revealed deletion abrogated antiangiogenic inflammasome-activated Conclusions: Taken together, these findings indicate deficiency promotes accelerating autolysosomal The mechanism action a potential target for therapeutic angiogenesis diseases.