Mechanistic insights into the mitigating role of dapagliflozin against radiation-triggered myocardial apoptosis: gating to AMPK-regulated autophagic machinery

Cardiovascular complications are a major, mortality-associated consequence of radiotherapy in breast and lung cancer patients. Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 inhibitor, has recently exhibited significant cardioprotective properties in cancer patients. The present study evaluated the cardioprotective efficacy and the underlying molecular mechanisms of DAPA in a rat model of radiation-induced cardiotoxicity. Male Sprague-Dawley rats were randomized into four groups: the first served as control; the second received DAPA (1 mg/kg, p.o. for 28 days); the third and fourth were exposed to 15 Gy acute thoracic γ-irradiation, with the fourth group receiving DAPA for 28 days post-irradiation. The deleterious effect of radiation on cardiac tissue was evidenced by marked histopathological alterations, increased heart index, elevated serum CK-MB levels, alongside ECG changes, including bradycardia and tall T waves, all of which were significantly alleviated by DAPA treatment. DAPA exhibited significant cardiac antioxidant properties, as reflected by reduced MDA and increased reduced glutathione levels. Mechanistically, DAPA mediated AMPK phosphorylation and enhanced autophagy-related responses following irradiation, as evidenced by increased expression of autophagy proteins (LC3, Beclin-1), upregulating the transcription of autophagy-related genes (ATG5, ATG7, ATG12), and decreased SQSTM1/p62 accumulation. This autophagic activation was accompanied by a blockage of intrinsic cardiomyocyte apoptosis triggered by radiation, as shown by decreased transcription of p53 and Bax while increased Bcl2, resulted in a reduced Bax/Bcl2 ratio and suppressed cleaved caspase-3 expression. In conclusion, DAPA confers cardio-protection against radiation injury by improving oxidative status and modulating the balance between apoptosis and adaptive autophagy, accompanied by increased AMPK phosphorylation.