Abstract

Vascular cell adhesion molecule 1 (VCAM-1), a known downstream target of the Forkhead box O (FoxO) family of transcription factors, has well-established roles in development, cell-cell interactions, and cell survival. However, the specific role and mechanisms whereby VCAM-1 governs cardiomyocyte homeostasis in ischemic heart disease are incompletely understood. Here, we report that ischemia/reperfusion (I/R)-induced myocardial damage resulted in marked attenuation of FoxO1 and Vcam1 mRNA levels in wild-type (WT) mice, suggesting a protective role of the FoxO1/VCAM-1 axis in I/R injury. Indeed, compared with WT littermates, cardiomyocyte-specific loss of Vcam1 significantly exacerbated I/R-induced myocardial damage, apoptotic cardiomyocyte death, contractile dysfunction, and maladaptive cardiac remodeling. We go on to show that after exposure to ischemia, Vcam1-deficient cardiomyocytes (both in vivo and in vitro) manifested marked attenuation of essential pro-survival cues. These include a decrease in the cardiomyocyte-leukocyte interaction-mediated induction of Ezrin and its downstream Akt and ERK1/2 phosphorylation, as well as decreased expression of tumor necrosis factor ? (TNF?) and manganese superoxide dismutase 2 (Sod2) genes. Collectively, our findings uncover a VCAM-1/Ezrin axis as an essential and previously unrecognized protective mediator of cardiomyocyte homeostasis in ischemic myocardium. © The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2025.