VSIG3 preserves mitochondrial homeostasis and restrains CD4⁺ T-Cell infiltration in myocardial ischemia-reperfusion injury through regulation of mitochondrial-derived vesicles.

Myocardial ischemia-reperfusion (MI/R) injury remains an inevitable and severe clinical challenge during cardiac surgery, primarily characterized by mitochondrial dysfunction and robust CD4+ T cell infiltration. In this study, we investigated the therapeutic potential of the immune checkpoint molecule VSIG3 (V-set and transmembrane domain-containing protein 3) in mitigating MI/R injury. In clinical samples, ELISA-detectable VSIG3-related plasma immunoreactivity of an undefined molecular form was associated with myocardial injury and inflammation. Recombinant VSIG3 administration improved cardiac function in MI/R mice and was accompanied by lower cardiac extracellular vesicle (EV) levels, including a reduction in TOMM20⁺ mitochondrial-derived vesicle (MDV)-related signals. In vitro, VSIG3 attenuated apoptosis, enhanced antioxidant capacity, and preserved mitochondrial metabolism, accompanied by an associated increase in PI3K/Akt/mTOR phosphorylation at 3 h post-injury. Exogenous MDV supplementation partially counteracted the cytoprotective effects observed with VSIG3 treatment. In vivo, VSIG3 treatment reduced CD4+ T cell infiltration and suppressed inflammatory cytokines (TNF-α, IL-17α, IL-21) in myocardial tissue. In summary, exogenous MDVs behaved as detrimental stimuli in the present experimental settings, whereas VSIG3 treatment was accompanied by reduced MDV release, improved mitochondrial homeostasis, and suppressed T-cell activation. These findings support an association between VSIG3 treatment and MDV-related changes in MI/R injury, but do not establish MDV suppression as a necessary or sufficient mediator of VSIG3-mediated cardioprotection.