UCF101 Rescues against Diabetes-Evoked Cardiac Remodeling and Contractile Anomalies through AMP-Activated Protein Kinase-Mediated Induction of Mitophagy.

<bold><italic>Introduction:</italic></bold> Diabetes mellitus is known to provoke devastating anomalies in myocardial structure and function, while effective therapeutic regimen is still lacking. The selective protease inhibitor UCF101 (5-[5-(2-nitrophenyl) furfuryl iodine]-1,3-diphenyl-2-thiobarbituric acid) has been shown to fend off ischemic heart injury, although its impact on diabetic cardiomyopathy remains elusive. <bold><italic>Methods:</italic></bold> Our present work was conducted to examine the effect of UCF101 on experimental diabetes-evoked cardiac geometric and functional abnormalities as well as mechanisms involved. Adult mice were made diabetic using streptozotocin (STZ, 50 mg/kg, i.p., for 5 days) while receiving UCF101 (7.15 mg/kg, i.p.). <bold><italic>Results:</italic></bold> STZ evoked cardiac hypertrophy, interstitial fibrosis, mitochondrial ultrastructural damage, oxidative stress, dampened autophagy (LC3B, Beclin 1, elevated p62), mitophagy (FUNDC1 and Parkin with upregulated TOM20), increased left ventricular end systolic diameter, reduced fractional shortening, ejection fraction, cardiomyocyte shortening capacity, velocities of shortening/re-lengthening, and rise in intracellular Ca2+ in conjunction with elongated diastole and intracellular Ca2+ removal, the responses were overtly reconciled by UCF101 with little effects from UCF101 itself. Levels of cell injury markers Omi/HtrA2, TNFα, and stress signaling (JNK, ERK, p38) were overtly enhanced along with compromised phosphorylation of cellular fuel AMP-activated protein kinase (AMPK) (Thr172) and cell survival molecule GSK3β, as well as downregulated SERCA2a and elevated phospholamban, the effect was reversed by UCF101 (except for SERCA2a). AMPK knockout, pharmacological inhibition, the mitophagy inhibitor liensinine, and parkin knockout nullified UCF101-offered cardioprotection in diabetes. UCF101 reversed STZ-induced upregulation in the AMPK degrading enzymes PP2A and PP2C. <bold><italic>Conclusion:</italic></bold> These findings suggest that UCF101 rescues diabetes-mediated alterations in cardiac structure and function, likely through AMPK-mediated regulation of mitophagy. [ABSTRACT FROM AUTHOR]