XML Attenuates Ox-LDL-Induced Endothelial Progenitor Cell Senescence via Gria2 and cAMP Pathways

In-stent restenosis (ISR) following percutaneous coronary intervention (PCI) is a critical clinical issue, often arising from endothelial injury and impaired repair mechanisms. Endothelial progenitor cells (EPCs), derived from bone marrow, play a key role in vascular health, but their function diminishes with aging and exposure to oxidised low-density lipoprotein (ox-LDL). This study investigates the potential of Xin-Mai-Long (XML), a traditional Chinese medicine used for chronic congestive heart failure, to delay EPC senescence and dysfunction induced by ox-LDL. Our findings demonstrate that XML administration significantly attenuates ox-LDL-induced EPC senescence and dysfunction. RNA sequencing identified Gria2 as a crucial gene downregulated by ox-LDL and restored by XML. Overexpression of Gria2 in EPCs similarly protected against ox-LDL-induced damage. Further analysis using Gene Ontology (GO) and KEGG enrichment revealed that the cAMP signalling pathway is significantly activated in response to XML and Gria2 overexpression. Notably, inhibition of cAMP with cis-Epoxysuccinic Acid (CESA) diminished the protective effects of XML and Gria2, underscoring the importance of this pathway. In vivo experiments using a rat carotid balloon injury model showed that both XML administration and transplantation of Gria2-overexpressing EPCs reduced vascular damage. These results suggest that XML mitigates EPC senescence and dysfunction by upregulating Gria2 and activating the cAMP signalling pathway, offering a promising therapeutic strategy for managing ISR after PCI.