1,25-Dihydroxyvitamin D attenuates diabetic cardiac autophagy and damage by vitamin D receptor-mediated suppression of FoxO1 translocation.

Cardiovascular abnormalities are one of the most important complications associated with diabetes. However, the effect of 1, 25-dihydroxyvitamin D (1,25D) on the diabetic heart and the associated regulatory mechanisms are not well appreciated. Here, we report that activation of the vitamin D receptor (VDR) by 1,25D depresses autophagic activity by inhibiting nuclear FoxO1 translocation to attenuate diabetic heart damage. Treatment with 1,25D improved oral glucose tolerance test outcomes, fasting blood glucose levels and CK-MB release in Zucker diabetic fatty (ZDF, fa/fa) rats. Moreover, 1,25D intervention decreased the expression of Bcl-2, Bax, cleaved caspase-3, nuclear FoxO1, LC3II/LC3I and Beclin1 in the hearts of ZDF rats. However, VDR was noticeably up-regulated by 1,25D, which was inhibited in diabetic hearts. In the cardiomyocyte cell line H9c2, further accumulation of LC3II and the augmentation of p62 after treatment with high glucose and chloroquine confirmed increased autophagic activity in diabetic hearts. Moreover, increased Bcl-2 and Bax levels were observed after treatment with an agonist (rapamycin) and antagonist (3MA) of autophagy in high-glucose-cultured cells. The knockdown of VDR with siRNA further induced the expression of LC3II and FoxO1 translocation and altered the Bax/Bcl-2 ratio in high-glucose-exposed cells, and these effects were suppressed by treatment with 1,25D or an inhibitor of FoxO1 transcriptional activity. In summary, 1,25D supplementation attenuated diabetic heart-related cardiac autophagy and damage by activating the VDR to inhibit the nuclear translocation of FoxO1.