RTA 408 ameliorates diabetic cardiomyopathy by activating Nrf2 to regulate mitochondrial fission and fusion and inhibiting NF-κB-mediated inflammation

Diabetic cardiomyopathy (dCM) is a major complication of diabetes; however, specific treatments for dCM are currently lacking. RTA 408, a semisynthetic triterpenoid, has shown therapeutic potential against various diseases by activating the Nrf2 (Nuclear factor erythroid 2-related factor 2) signaling pathway. We established in vitro and in vivo models using high-glucose toxicity and db/db mice, respectively, to simulate dCM. Our results demonstrated that RTA 408 activated Nrf2 and alleviated various dCM-related cardiac dysfunctions, both in vivo and in vitro. Additionally, it was found that silencing the Nrf2 gene eliminated the cardioprotective effect of RTA 408. RTA 408 ameliorated oxidative stress in dCM mice and HG-exposed H9C2 cells by activating Nrf2, inhibiting mitochondrial fission, exerting anti-inflammatory effects through the Nrf2/NF-κB axis, and ultimately suppressing Apoptosis, thereby providing cardiac protection against dCM. These findings provide valuable insights for potential dCM treatments.

Diabetic cardiomyopathy; Mitochondrial fission and fusion; Nrf2; Oxidative stress; RTA 408.