Exosomal MALAT1 expression associated with the cardioprotective effects of carvacrol in acute doxorubicin-induced cardiac injury: Potential involvement of Nrf2/Keap1-related signaling.

Doxorubicin remains an indispensable component of many chemotherapy regimens; however, its clinical use is limited by dose-dependent cardiotoxicity that may progress to dilated cardiomyopathy and heart failure. In the present study, we investigated the effects of the phytochemical carvacrol on cardiac function, apoptosis, and Nrf2/Keap1-related gene expression, as well as its association with extracellular vesicle-associated MALAT1 expression. Rats received oral carvacrol treatment for two weeks prior to a single 20 mg/kg doxorubicin injection to induce acute cardiac injury. Cardiac function and myocardial apoptosis were evaluated two days after doxorubicin administration. H9c2 cardiomyoblast cells were exposed to co-treatment or pretreatment protocols using carvacrol (50, 100, and 300 µM) in combination with 0.5 µM doxorubicin. Nrf2, Keap1, and extracellular vesicle-associated MALAT1 expression levels were evaluated using quantitative PCR. Caspase-3/7 activity was also assessed as an indicator of apoptotic activity. Doxorubicin treatment impaired cardiac function, increased apoptotic activity in myocardial tissue and H9c2 cells, upregulated Keap1 expression, and reduced Nrf2 transcript levels. Carvacrol treatment reduced apoptotic activity, improved cardiac functional parameters, downregulated Keap1 expression, and increased Nrf2 and extracellular vesicle-associated MALAT1 expression, with pretreatment protocols showing comparatively greater protective effects. These findings suggest that carvacrol may attenuate acute doxorubicin-induced cardiac injury in association with modulation of Nrf2/Keap1-related gene expression and altered extracellular vesicle-associated MALAT1 levels. Further mechanistic studies are required to clarify the functional role of exosomal MALAT1 in these effects.