KLF5 Is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy

• Published in: Circulation research Vol. 128; no. 3; pp. 335 - 357
• Main Authors: Kyriazis, Ioannis D, Hoffman, Matthew, Gaignebet, Lea, Lucchese, Anna Maria, Markopoulou, Eftychia, Palioura, Dimitra, Wang, Chao, Bannister, Thomas D, Christofidou-Solomidou, Melpo, Oka, Shin-Ichi, Sadoshima, Junichi, Koch, Walter J, Goldberg, Ira J, Yang, Vincent W, Bialkowska, Agnieszka B, Kararigas, Georgios, Drosatos, Konstantinos
• Format: Journal Article
• Language: English
• Published: United States 05.02.2021
• Subjects: Aged; Animals; Cell Line; Diabetic Cardiomyopathies - genetics; Diabetic Cardiomyopathies - metabolism; Diabetic Cardiomyopathies - pathology; Disease Models, Animal; Female; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Gene Expression Regulation; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Oxidative Stress; PPAR alpha - genetics; PPAR alpha - metabolism; Transcription, Genetic; forkhead box protein O1; diabetic cardiomyopathy; NADPH oxidases; peroxisome proliferator-activated receptors; ceramides; oxidative stress
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/circresaha.120.316738

Diabetic cardiomyopathy (DbCM) is a major complication in type-1 diabetes, accompanied by altered cardiac energetics, impaired mitochondrial function, and oxidative stress. Previous studies indicate that type-1 diabetes is associated with increased cardiac expression of KLF5 (Krüppel-like factor-5) and PPARα (peroxisome proliferator-activated receptor) that regulate cardiac lipid metabolism. In this study, we investigated the involvement of KLF5 in DbCM and its transcriptional regulation. KLF5 mRNA levels were assessed in isolated cardiomyocytes from cardiovascular patients with diabetes and were higher compared with nondiabetic individuals. Analyses in human cells and diabetic mice with cardiomyocyte-specific FOXO1 (Forkhead box protein O1) deletion showed that FOXO1 bound directly on the promoter and increased KLF5 expression. Diabetic mice with cardiomyocyte-specific FOXO1 deletion had lower cardiac KLF5 expression and were protected from DbCM. Genetic, pharmacological gain and loss of KLF5 function approaches and AAV (adeno-associated virus)-mediated delivery in mice showed that KLF5 induces DbCM. Accordingly, the protective effect of cardiomyocyte FOXO1 ablation in DbCM was abolished when KLF5 expression was rescued. Similarly, constitutive cardiomyocyte-specific KLF5 overexpression caused cardiac dysfunction. KLF5 caused oxidative stress via direct binding on NADPH oxidase ( )4 promoter and induction of NOX4 (NADPH oxidase 4) expression. This was accompanied by accumulation of cardiac ceramides. Pharmacological or genetic KLF5 inhibition alleviated superoxide formation, prevented ceramide accumulation, and improved cardiac function in diabetic mice. Diabetes-mediated activation of cardiomyocyte FOXO1 increases KLF5 expression, which stimulates NOX4 expression, ceramide accumulation, and causes DbCM.