UCF-101 Ameliorates Streptozotocin-Induced Cardiomyocyte Contractile Dysfunction in vitro: Role of AMP-Activated Protein Kinase. Experimental physiology [Exp Physiol] Journal article

UCF-101, 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid, is a protease inhibitor which was reported to protect against ischemic heart damage and apoptosis. This study evaluated the impact of UCF-101 on steptozotocin (STZ)-induced diabetic cardiomyocyte dysfunction. Adult FVB mice were made diabetic with a single injection of STZ (200 mg/kg). Two weeks after STZ injection, cardiomyocytes from control and STZ mice were isolated and treated with UCF-101 (20 microM for 1 hr). Cardiomyocyte contractile properties were analyzed including peak shortening (PS), maximal velocity of shortening/relengthening (+/- dL/dt), time-to-PS (TPS) and time-to-90% relengthening (TR90). STZ-induced diabetes depressed PS, +/- dL/dt, prolonged TPS and TR90 in cardiomyocytes, all of which were significantly alleviated by UCF-101. Immunoblotting analysis showed that UCF-101 significantly alleviated STZ-induced loss of phospholamban phosphorylation without affecting SERCA2a and phospholamban. STZ reduced AMPK phosphorylation at Thr172 of catalytic subunit without affecting total AMPK expression, which was restored by UCF-101. Short-term UCF-101 exposure did not change the expression of XIAP and Omi/HtrA2, favoring an apoptosis-independent mechanism. Both the AMPK activator resveratrol and the antioxidant N-acetylcysteine mimicked UCF-101-induced beneficial effect in STZ-induced diabetic cardiomyocytes. In addition, UCF-101 promoted the phosphorylation of p38 and JNK after 15 min of incubation where it failed to affect the phosphorylation of ERK and GSK-3beta within 120 min in H9C2 myoblasts. Taken together, these results indicate that UCF-101 protects against STZ-induced cardiomyocyte contractile dysfunction, possibly via an AMPK-associated mechanism.

Experimental physiology [Exp Physiol]