UCF- 101 mitigates streptozotocin-induced cardiomyocyte dysfunction: role of AMPK.

Diabetic heart disease contributes to the high mortality in diabetics, although effective clinical management is lacking. The protease inhibitor 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) was reported to protect the hearts against ischemic injury. This study examined the role of UCF101 on streptozotocin (STZ)-induced diabetic heart defect. Vehicle or UCF101 was administrated to STZ diabetic mice, and cardiomyocyte mechanical properties were analyzed. UCF101 reduced STZ-induced hyperglycemia and alleviated STZ-induced aberration in cardiomyocyte contractile mechanics. Diabetes dramatically decreased AMPK phosphorylation at Thr¹⁷² of catalytic α-subunit, which was restored by UCF101. Neither diabetes nor UCF-101 affected the expression of HtrA2/Omi and XIAP or caspase-3 activity. The AMPK activator resveratrol mimicked the UCF-101-induced beneficial effect against diabetic cardiac dysfunction. Mechanical properties in cardiomyocytes from the AMPK kinase-dead (1(D) mice displayed markedly impaired contractile function reminiscent of diabetes. STZ injection in AMPK-KD mice failed to elicit any additional cardiomyocyte contractile defect. UCF101 significantly downregulated the AMPK-degrading enzymes PP2A and PP2C, the effect of which was mimicked by resveratrol. Taken together, these results indicate that UCF101 protects against STZ-induced cardiac dysfunction, possibly through AMPK signaling. [ABSTRACT FROM AUTHOR]