1. Retraction: ‘The protease inhibitor UCF-101 ameliorates streptozotocin-induced mouse cardiomyocyte contractile dysfunction in vitro: role of AMP-activated protein kinase’
- Author
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Qun Li, Jun Ren, and Lindsay K. Hueckstaedt
- Subjects
Male ,medicine.medical_specialty ,Physiology ,MAP Kinase Signaling System ,p38 mitogen-activated protein kinases ,X-Linked Inhibitor of Apoptosis Protein ,Pyrimidinones ,AMP-Activated Protein Kinases ,In Vitro Techniques ,Article ,Antioxidants ,Streptozocin ,Diabetes Mellitus, Experimental ,Sarcoplasmic Reticulum Calcium-Transporting ATPases ,Diabetes Complications ,Mitochondrial Proteins ,Mice ,AMP-activated protein kinase ,Physiology (medical) ,Internal medicine ,Stilbenes ,medicine ,Animals ,Myocytes, Cardiac ,Protease Inhibitors ,Glycogen synthase ,Protein kinase A ,Nutrition and Dietetics ,biology ,Kinase ,Calcium-Binding Proteins ,Serine Endopeptidases ,AMPK ,Thiones ,General Medicine ,High-Temperature Requirement A Serine Peptidase 2 ,Myocardial Contraction ,Phospholamban ,Acetylcysteine ,Endocrinology ,Resveratrol ,biology.protein ,Phosphorylation ,Cardiomyopathies - Abstract
5-[5-(2-Nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) is a protease inhibitor which was reported to protect against ischaemic 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(1)). Two weeks after STZ injection, cardiomyocytes from control and STZ-treated mice were isolated and treated with UCF-101 (20 mum for 1 h). Cardiomyocyte contractile properties were analysed, including peak shortening (PS), maximal velocity of shortening/relengthening (+/-dL/dt), time to PS (TPS) and time to 90% relengthening (TR(90)). Steptozotocin-induced diabetes depressed PS and +/-dL/dt and prolonged TPS and TR(90) 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 sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban. Steptozotocin reduced AMP-activated protein kinase (AMPK) phosphorylation at Thr172 of the catalytic subunit without affecting total AMPK expression, which was restored by UCF-101. Short-term exposure to UCF-101 did not change the expression of X-linked inhibitor of apoptosis protein (XIAP) and Omi stress-regulated endoprotease, high temperature requirement protein A2 (Omi/HtrA2), favouring an apoptosis-independent mechanism. Both the AMPK activator resveratrol and the antioxidant N-acetylcysteine mimicked the UCF-101-induced beneficial effect in STZ-induced diabetic cardiomyocytes. In addition, UCF-101 promoted the phosphorylation of p38 mitogen-activated protein kinases and c-Jun N-terminal kinase (JNK) after 15 min of incubation, while it failed to affect the phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase kinase-3beta (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.
- Published
- 2022