L-Arginine effectively alleviates doxorubicin-induced cardiac dysfunction by inhibiting myocardial fibrosis

The clinical use of doxorubicin (DOX), a widely used and effective antitumor drug, is limited by its cardiotoxicity. Currently, safe and effective strategies for preventing doxorubicin-induced cardiotoxicity (DIC) remain limited. Therefore, this study aimed to investigate the potential cardioprotective effects and possible underlying mechanisms of L-arginine (L-Arg) against DIC.

To investigate the cardioprotective effects and underlying mechanisms of L-Arg, three complementary experimental models were used: male Sprague-Dawley rats (n = 6 per group), male AMPKα2 knockout (AMPKα2 KO) mice (n = 6 per group), and H9c2 cardiomyocytes. A DIC model was induced in rats by intraperitoneal injection of DOX (2.5 mg/kg/week) for 6 weeks. Serum nitric oxide (NO) and lactate dehydrogenase (LDH) levels were measured to assess oxidative stress and myocardial injury. Cardiac morphology, inflammation, and fibrosis were evaluated by histological staining and protein expression analyses, whereas miR-29b-3p expression was determined by RT-qPCR. AMPKα2-deficient models and miR-29b-3p gain- and loss-of-function models were used to investigate the underlying mechanisms. Compared with the DOX group, L-Arg significantly improved cardiac function and morphology, reduced oxidative stress, myocardial injury, inflammation, and fibrosis, and increased miR-29b-3p expression (all P < 0.05). Moreover, miR-29b-3p overexpression enhanced, whereas miR-29b-3p inhibition attenuated, the cardioprotective effects of L-Arg (all P < 0.05). These protective effects were also markedly attenuated by AMPKα2 deficiency (P < 0.05).

L-Arg alleviates DIC by improving cardiac function, reducing oxidative stress, inflammation, and fibrosis, and increasing miR-29b-3p expression. These cardioprotective effects are associated with AMPKα2 activation and enhanced miR-29b-3p expression.