TRPA1 deficiency attenuates cardiac fibrosis via regulating GRK5/NFAT signaling in diabetic rats

Abstract Diabetic cardiac fibrosis increases ventricular stiffness and promotes diastolic dysfunction. The transient receptor potential ankyrin 1 (TRPA1) has been reported to be associated with the occurrence and development of various cardiovascular diseases. However, the role of sperm TRPA1 in diabetic cardiomyopathy (DCM) remains unclear. Here, we investigated the cardioprotective effects of TRPA1 deficiency on DCM in streptozotocin (STZ)-induced diabetic rats and in neonatal rat cardiac fibroblasts (CFs) incubated with high glucose (HG). The results showed that the expression of TRPA1 was increased in the cardiac tissue of diabetic rats and in CFs treated with HG. TRPA1 deficiency significantly ameliorated cardiac dysfunction in diabetic rats, characterized by improved echocardiography and reduced cardiac hypertrophy and fibrosis. In vitro, TRPA1 deficiency suppressed HG-induced activation and transdifferentiation of CFs. Mechanistically, the cardioprotective effect of TRPA1 deficiency inhibited cardiac fibrosis by regulating GRK5/NFAT signaling. Furthermore, inhibition of GRK5/NFAT signaling abolished TRPA1 activation-induced transdifferentiation of CFs. For further clinical translation, we utilized 1,8-cineole (CIN), a natural inhibitor of TRPA1, to treat DCM. Inhibition of TRPA1 activation by CIN attenuated cardiac dysfunction and remodeling in diabetic rats by regulating GRK5/NFAT signaling. Taken together, these results suggest that TRPA1 deletion protects against DCM in vivo and in vitro by regulating GRK5/NFAT signaling. TRPA1 inhibitor CIN may serve as novel therapeutic agents for the treatment of DCM.