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 UCF-101 on streptozotocin (STZ)-induced diabetic heart defect. Vehicle or UCF-101 was administrated to STZ diabetic mice, and cardiomyocyte mechanical properties were analyzed. UCF-101 reduced STZ-induced hyperglycemia and alleviated STZ-induced aberration in cardiomyocyte contractile mechanics. Diabetes dramatically decreased AMPK phosphorylation at Thr(172) of catalytic alpha-subunit, which was restored by UCF-101. 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 (KD) mice displayed markedly impaired contractile function reminiscent of diabetes. STZ injection in AMPK-KD mice failed to elicit any additional cardiomyocyte contractile defect. UCF-101 significantly downregulated the AMPK-degrading enzymes PP2A and PP2C, the effect of which was mimicked by resveratrol. Taken together, these results indicate that UCF-101 protects against STZ-induced cardiac dysfunction, possibly through AMPK signaling.
Li
Qun
Q
Division of Pharmaceutical Sciences, University of Wyoming, Laramie, WY 82071, USA.
Li
Ji
J
Ren
Jun
J
D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002469:Cell Separation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013871:Thiones / Q000494:pharmacology*
D000975:Antioxidants; D001786:Blood Glucose; D007527:Isoenzymes; D011480:Protease Inhibitors; D011744:Pyrimidinones; D013267:Stilbenes; D013871:Thiones; C501517:UCF 101; D000263:Adenylate Kinase; D054648:Protein Phosphatase 2; D053148:Caspase 3; D000077185:Resveratrol
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