Brown adipose tissue-derived sEV-lncRNA Morrbid contributes to cold acclimation-induced cardioprotection against...

Extreme cold causes myocardial injury; however, cold acclimation (CA) enhances myocardial tolerance. This study investigated whether brown adipose tissue (BAT)-derived extracellular vesicles (BAT-EVs) contribute to CA-induced cardioprotection. Mice were subjected to CA or acute cold stress. Cardiac function was assessed using echocardiography and biomarkers. Interscapular BAT (iBAT) ablation has confirmed the necessity of iBAT. EVs were characterized and tested in HL-1 cardiomyocytes. Transcriptomics and specific gene knockdowns have identified key molecular mechanisms. CA preserved cardiac function and integrity under -25°C stress, and these effects were abolished by iBAT ablation. EVs from CA mice mediate this protection by mitigating cardiomyocyte apoptosis. Mechanistically, lncRNA Morrbid was enriched in iBAT and serum EVs after CA. iBAT-specific Morrbid knockdown significantly attenuates EV-mediated protection. Furthermore, Morrbid was associated with upregulation of Serpine1 in cardiomyocytes; silencing Serpine1 abolished anti-apoptotic benefits. This study identified a BAT-Heart axis where CA stimulates the release of Morrbid-enriched EVs. These vesicles serve as a mechanism to confer remote cardioprotection, potentially by upregulating cardiac Serpine1 and suppressing apoptosis.