Background
The severe unfavorable effects of doxorubicin on the heart restrict its clinical usage. Numerous investigations document that cyclic GMP-AMP synthase (cGAS) activator of interferon genes (STING) cascade influences inflammation along with the immune response in a variety of diseases. The pathophysiological function of the cGAS-STING cascade in Doxorubicin-induced cardiomyopathy (DIC) is, nevertheless, unknown.
Conclusion
This research premise established that STING inhibition could alleviate Dox-triggered cardiotoxicity in mice. As a result, preventing DIC by repressing STING in cardiomyocytes might be a possible treatment approach.
Methods
In vivo, cardiotoxicity was triggered by a single dose of intra-peritoneal inoculation of doxorubicin (15 mg/kg) in wild-type C57BL/6J mice and STING knockdown animals. Adeno-associated virus 9 (AAV9) was utilized to silence STING. qPCR along with Western blotting were adopted to assess alterations in the cGAS/STING cascade. To assess cardiac function, we employed echocardiography coupled with histology, as well as molecular phenotyping. In vitro, HL-1 cardiomyocytes were introduced as test models.
Results
In wild type mice, doxorubicin stimulation significantly activated the cGAS/STING pathway. STING silencing increased rate of survival along with heart function in mice, as well as diminished myocardial inflammatory cytokines along with apoptosis. These observations were also confirmed by utilizing siRNA of STING in vitro studies.