Olfactory Receptor 2 in Monocytes Exacerbates Myocardial Ischemia-Reperfusion Injury via Drp1-Dependent Mitochondrial Fission Mediated by NR4A1

Myocardial ischemia-reperfusion (I/R) injury represents a major clinical challenge with limited therapeutic options. This study examines the role of Olfactory Receptor 2 (Olfr2) in monocytes during myocardial I/R injury. We utilized RNA sequencing to analyze monocytes isolated from the spleens of wild-type (WT) mice, investigating their response to low-dose LPS priming and subsequent treatment with octanal (Oct), a specific agonist of Olfr2. Principal component analysis (PCA) revealed distinct clustering among experimental groups, highlighting significant gene expression changes in pathways related to cAMP/PKA signaling and inflammasome activation. Notably, the low-dose LPS+Oct treatment induced substantial upregulation of genes such as Adcy, Pka, Nlrp3, Pycard, Casp4, Gsdmd, and Nr4a1. Moreover, monocytes subjected to low-dose LPS+Oct exhibited increased expression of pro-inflammatory cytokines (IL-1β, IL-12a, IL-18, and TNF), chemokines (CCL3, CCL4, CXCL1, CXCL2, and CXCL3), and demonstrated enrichment in pathways associated with oxidative stress, positive chemotaxis, and the production and secretion of inflammatory cytokines (IL-1β, IL-8, TNF). To elucidate the role of Olfr2 in monocytes during myocardial I/R injury, we subjected mouse spleen-derived monocytes to three treatment conditions: (1) low-dose LPS stimulation (40 ng/ml for 5 hours), (2) low-dose LPS priming followed by octanal administration (20 µM for 18 hours), and (3) an untreated control with DMSO (1:1000).