The mechanisms and therapeutic potential of clopidogrel in mitigating diabetic cardiomyopathy in db/db mice

Clopidogrel has been shown to play a protective role against diabetic nephropathy. However, whether clopidogrel exerts a protective effect against diabetic cardiomyopathy (DCM) is unknown. Three-month-old male db/db mice were administered clopidogrel daily at doses of 5, 10, and 20 mg/kg by gavage for 5 months. Here, we showed that clopidogrel effectively attenuated diabetes-induced cardiac hypertrophy and cardiac dysfunction by inhibiting cardiac fibrosis, inflammatory responses, and oxidative stress damage in db/db mice. Diabetes-induced cardiac fibrosis was inhibited by clopidogrel treatment via blockade of the TGF-β1/SMAD3/P2RY12 pathway and inhibition of macrophage infiltration in db/db mice. The protective effects of clopidogrel against oxidative damage were mediated by the induction of the Nrf2 signaling pathway. Taken together, our findings provide strong evidence that clopidogrel is a promising effective agent for the treatment of DCM by alleviating diabetes-induced cardiac hypertrophy and dysfunction. P2RY12 might be an effective target for the treatment of DCM.