GLIPR2 regulates EndoMT and cardiac fibrosis after AMI via PDGFRL/AKT/mTOR signaling pathway

The endothelium-mesenchymal transition (EndoMT) is a pivotal mechanism in cardiac fibrosis following acute myocardial infarction (AMI), as endothelial cells are a primary source of interstitial stromal cells contributing to organ fibrosis. Glioma pathogenesis-related protein 2(GLIPR2) has been reported to be associated with EndoMT, but whether it can regulate cardiac fibrosis is unknown. This study aimed to explore the contribution of GLIPR2 to post-AMI fibrosis and its underlying mechanism.

Serum protein levels of GLIPR2 were measured in patients with AMI. LAD ligation surgery was used to establish AMI animal models in C57BL/6 J mice. Adeno-associated virus (AAV)-targeted knockdown of GLIPR2 was employed to investigate the effects of GLIPR2 on cardiac fibrosis, cardiac pumping function, and EndoMT after AMI in mice. In human cardiac microvascular endothelial cells (HCMECs), GLIPR2 overexpression and knockdown via lentivirus (LV) were utilized to examine angiogenesis, migration, proliferation, and EndoMT under hypoxic conditions.

In the serum of AMI patients, GLIPR2 expression was significantly increased. In mice with AMI, GLIPR2 knockdown reversed EndoMT, attenuated heart fibrosis, and partially restored ventricular pumping function. In a hypoxic cell model, GLIPR2 overexpression enhanced cell proliferation, migration, neovascularization, and EndoMT, whereas GLIPR2 knockdown inhibited these processes. Furthermore, transcriptome sequencing and recovery studies identified the platelet-derived growth factor receptor-like protein (PDGFRL)/AKT/mTOR pathway as a critical regulator of GLIPR2-mediated EndoMT.

GLIPR2 promotes cardiac fibrosis repair by regulating EndoMT through the PDGFRL/AKT/mTOR signaling pathway. Its inhibition represents a potential therapeutic strategy to mitigate cardiac fibrosis and improve ventricular function following AMI.