as-1842856 and Disease-Models--Animal

Topics: Angiotensin II; Animals; Apoptosis; Autophagy; Blood Glucose; Cell Line; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Disease Models, Animal; Fibrosis; Forkhead Box Protein O1; Glucose; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Oxidative Stress; Quinolones; Signal Transduction; Streptozocin; Ventricular Dysfunction, Left

Growing evidence indicates targeting mitochondrial dynamics and biogenesis could accelerate recovery from renal ischemia-reperfusion (I/R) injury, but the underlying mechanisms remain elusive. Transcription factor forkhead box O1 (FOXO1) is a key regulator of mitochondrial homeostasis and plays a pathological role in the progression of renal disease.. A mouse model of renal I/R injury and a hypoxia/reoxygenation (H/R) injury model for human renal tubular epithelial cells were used.. I/R injury up-regulated renal expression of FOXO1 and treatment with FOXO1-selective inhibitor AS1842856 prior to I/R injury decreased serum urea nitrogen, serum creatinine and the tubular damage score after injury. Post-I/R injury AS1842856 treatment could also ameliorate renal function and improve the survival rate of mice following injury. AS1842856 administration reduced mitochondrial-mediated apoptosis, suppressed the overproduction of mitochondrial ROS and accelerated recovery of ATP both in vivo and in vitro. Additionally, FOXO1 inhibition improved mitochondrial biogenesis and suppressed mitophagy. Expression of PPAR-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis, was down-regulated in both I/R and H/R injury, which could be abrogated by FOXO1 inhibition. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that FOXO1 inhibited PGC-1α transcription by competing with cAMP-response element binding protein (CREB) for its binding to transcriptional coactivators CREBBP/EP300 (CBP/P300).. These findings suggested that FOXO1 was critical to maintain mitochondrial function in renal tubular epithelial cells and FOXO1 may serve as a therapeutic target for pharmacological intervention in renal I/R injury.

Topics: Animals; Apoptosis; Cell Line; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Forkhead Box Protein O1; Humans; Kidney Diseases; Kidney Tubules; Male; Mice, Inbred C57BL; Mitochondria; Mitophagy; Organelle Biogenesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Quinolones; Reperfusion Injury; Signal Transduction

Recent clinical investigations indicate that anthracycline-based chemotherapies induce early decline in heart mass in cancer patients. Heart mass decline may be caused by a decrease in cardiac cell number because of increased cell death or by a reduction in cell size because of atrophy. We previously reported that an anthracycline, doxorubicin (DOX), induces apoptotic death of cardiomyocytes by activating cyclin-dependent kinase 2 (CDK2). However, the signaling pathway downstream of CDK2 remains to be characterized, and it is also unclear whether the same pathway mediates cardiac atrophy. Here we demonstrate that DOX exposure induces CDK2-dependent phosphorylation of the transcription factor forkhead box O1 (FOXO1) at Ser-249, leading to transcription of its proapoptotic target gene, Bcl-2-interacting mediator of cell death (Bim). In cultured cardiomyocytes, treatment with the FOXO1 inhibitor AS1842856 or transfection with FOXO1-specific siRNAs protected against DOX-induced apoptosis and mitochondrial damage. Oral administration of AS1842856 in mice abrogated apoptosis and prevented DOX-induced cardiac dysfunction. Intriguingly, pharmacological FOXO1 inhibition also attenuated DOX-induced cardiac atrophy, likely because of repression of muscle RING finger 1 (MuRF1), a proatrophic FOXO1 target gene. In conclusion, DOX exposure induces CDK2-dependent FOXO1 activation, resulting in cardiomyocyte apoptosis and atrophy. Our results identify FOXO1 as a promising drug target for managing DOX-induced cardiotoxicity. We propose that FOXO1 inhibitors may have potential as cardioprotective therapeutic agents during cancer chemotherapy.

Topics: Animals; Apoptosis; Atrophy; Cardiotoxicity; Cyclin-Dependent Kinase 2; Disease Models, Animal; Doxorubicin; Forkhead Box Protein O1; Gene Expression Regulation; Heart; Humans; Mice; Muscle Proteins; Myocytes, Cardiac; Neoplasms; Quinolones; Signal Transduction; Tripartite Motif Proteins; Ubiquitin-Protein Ligases

Forkhead box protein O1 (FOXO1), a nuclear transcription factor, is preferably activated in the myocardium of diabetic mice. However, its role and mechanism in the development of diabetic cardiomyopathy in non-obese insulin-deficient diabetes are unclear. We hypothesized that cardiac FOXO1 over-activation was attributable to the imbalanced myocardial oxidative metabolism and mitochondrial and cardiac dysfunction in type 1 diabetes. FOXO1-selective inhibitor AS1842856 was administered to streptozotocin-induced diabetic (D) rats, and cardiac functions, mitochondrial enzymes PDK4 and CPT1 and mitochondrial function were assessed. Primary cardiomyocytes isolated from non-diabetic control (C) and D rats were treated with or without 1 µM AS1842856 and underwent Seahorse experiment to determine the effects of glucose, palmitate and pyruvate on cardiomyocyte bioenergetics. The results showed diabetic hearts displayed elevated FOXO1 nuclear translocation, concomitant with cardiac and mitochondrial dysfunction (manifested as elevated mtROS level and reduced mitochondrial membrane potential) and increased cell apoptosis (all P < .05, D vs C). Diabetic myocardium showed impaired glycolysis, glucose oxidation and elevated fatty acid oxidation and enhanced PDK4 and CPT1 expression. AS1842856 attenuated or prevented all these changes except for glycolysis. We concluded that FOXO1 activation, through stimulating PDK4 and CPT1, shifts substrate selection from glucose to fatty acid and causes mitochondrial and cardiac dysfunction.

Topics: Animals; Apoptosis; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Disease Models, Animal; Disease Susceptibility; Energy Metabolism; Fatty Acids; Forkhead Box Protein O1; Gene Expression Regulation; Glucose; Glycolysis; Male; Membrane Potential, Mitochondrial; Mitochondria; Myocytes, Cardiac; Oxidation-Reduction; Oxidative Stress; Protein Transport; Quinolones; Rats; Ventricular Function, Left