Gu, X.-s. | bioRxiv Science

bioRxiv2024

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

molecular biology↗

bioRxiv2024

METTL3 Modulates Radiation-Induced Cardiac Fibrosis via the Akt/mTOR Pathway

BACKGROUNDRadiation therapy for cancer treatment frequently leads to radiation-induced heart disease (RIHD), characterized as cardiac fibrosis and heart failure. The enzyme METTL3, a key player in RNA methylation, is known to influence various cellular processes, while its specific role and mechanism in RIHD are not well understood. OBJECTIVESThe purpose of this study was to explore the potential mechanism of METTL3 in regulating cardiac fibrosis induced by radiation. METHODSWe constructed an X-ray-modulated RIHD mice models to investigate the role of METTL3 in cardiac fibroblasts. In parallel, METTL3 overexpression and silence were conducted on fibroblasts and mice heart to evaluate pro-fibrotic protein expression, cardiac fibrosis, and heart function. RESULTSElevated METTL3 expression was observed in both irradiated cardiac tissues and fibroblasts. Moreover, overexpression of METTL3 in cardiac fibroblasts was associated with increased expression of pro-fibrotic proteins and exacerbated fibrosis, whereas METTL3 silencing attenuated these adverse effects. Likewise, METTL3 knockdown ameliorated cardiac dysfunction and reduced fibrosis. Taken together, METTL3 could induce cardiac fibrosis via activating the Akt/mTOR signaling pathway to promote fibroblast proliferation and myofibroblast differentiation. CONCLUSIONSMETTL3 is a critical of RICD through modulating the Akt/mTOR pathway, hence targeting METTL3 presents a promising therapeutic strategy to mitigate the adverse cardiac effects of radiation therapy in cancer patients.

bioinformatics↗