NLGN3 contributes to angiogenesis in myocardial infarction via activation of the Gαi1/3-Akt Pathway

BACKGROUNDAngiogenesis is an important repair mechanism for myocardial infarction. Neuroligin-3 (NLGN3) can promote angiogenesis by activating Gi1/3-Akt signaling following ischemic brain injury. This study investigated the role of NLGN3 in myocardial infarction (MI). METHODS AND RESULTSOn the 7th day after MI, the plasma level of NLGN3 in patients was significantly higher than in the control group. A mouse model of MI also showed significantly increased expression of NLGN3 in heart tissue. Single-nucleus transcriptome analysis revealed that NLGN3 was located predominantly in cardiac fibroblasts and endothelial cells (ECs). Endothelial-specific knockdown of NLGN3, or inhibition of NLGN3 using ADAM10i, significantly increased the ischemic area, reduced angiogenesis, and worsened cardiac function. Co-immunoprecipitation (Co-IP) experiments showed that NLGN3 interacted with Gi1/3. The Gi1/3 knockout (Gi1/3-KO) mouse model of MI showed an increased ischemic area, decreased angiogenesis, and impaired cardiac function. Mechanistic studies showed that the NLGN3-Gi1/3 signaling pathway exerts cardioprotective effects by promoting EC proliferation and tube formation through the PI3K-Akt-mTOR pathway. Silencing of Gi1/3 largely eliminated the ability of NLGN3-promoting cardiac ECs to proliferate and form tubes. CONCLUSIONOur findings suggest the endothelial NLGN3-Gi1/3 signaling pathway promotes angiogenesis and reduces the ischemic area following MI, which is critical for maintaining cardiac function and repairing tissues. Targeting of the NLGN3-Gi1/3 signaling pathway may have clinical therapeutic potential in protecting the heart from ischemic injury. What Is Known?O_LIMyocardial infarction (MI) leads to a significantly increased risk of recurrent events in individually vascularized regions, which then stimulates adverse systemic vascular effects. C_LIO_LIGi proteins play a key role in receptor tyrosine kinase (RTK) and other non-GPCR receptor-mediated signaling. C_LIO_LINeuroligin 3 (NLGN3) is a major member of the NLGN family of proteins that help to form synapses between neurons. It is known be cleaved and secreted in an activity-dependent manner, but its function in heart disease is still poorly understood. C_LI What New Information Does This Article Contribute?O_LINLGN3 expression was found to be markedly increased in the heart after MI, especially in cardiac ECs. C_LIO_LIKnockdown of Gi1/3 significantly reduced angiogenesis and impaired cardiac function, while knockdown of NLGN3 increased the ischemic area and reduced angiogenesis through Gi1/3. C_LIO_LINLGN3-Gi1/3 signaling promotes vascular EC proliferation and tube formation through the PI3K-Akt-mTOR pathway, thereby protecting the ischemic heart. C_LI