PCSK9 inhibitor protects against ischemic cerebral injury by attenuating inflammation via the GPNMB/CD44 pathway

Abstract

BackgroundIschemic stroke is the second leading cause of death worldwide, and neuroinflammation has been recognized as a critical player in its progression. Meanwhile, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) has been demonstrated to inhibit inflammatory response. However, the effects of PCSK9i on ischemic stroke remain unclear and require further investigation. MethodsTemporary middle cerebral artery occlusion (tMCAO) was performed to establish animal models of ischemic stroke in C57BL/6 mice. The PCSK9i were administered subcutaneously after 2 h tMCAO. Neurological function and cerebral infarct volume were measured by mNSS and TTC staining, respectively. RNA-seq was performed to investigate the changes in mechanistic pathways. Western blotting and immunofluorescence were applied to detect expression of GPNMB, CD44, IL-6, and iNOS. ResultsTreatment with PCSK9i significantly improved neurological deficits and reduced the volume of cerebral infarction. PCSK9i suppressed neuroinflammation by activating the GPNMB/CD44 signaling pathway, further exerting their protective effects. ConclusionTaken together, treatment with PCSK9i is an effective way to prevent ischemic stroke-induced brain injury.