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

Abstract

Rationale: Diabetic cardiomyopathy (DbCM) is a major complication in type-1 diabetes (T1D), accompanied by altered cardiac energetics, impaired mitochondrial function and oxidative stress. Previous studies indicate that T1D is associated with increased cardiac expression of Krüppel-like factor-5 (KLF5) and Peroxisome Proliferator Activated Receptor (PPAR)α that regulate cardiac lipid metabolism. Objective: In this study, we investigated the involvement of KLF5 in DbCM and its transcriptional regulation. Methods and Results: KLF5 mRNA levels were assessed in isolated cardiomyocytes from cardiovascular patients with diabetes and was higher compared with non-diabetic individuals. Analyses in human cells and diabetic mice with cardiomyocyte-specific FOXO1 deletion showed that FOXO1 bound directly on the KLF5 promoter and increased KLF5 expression. Diabetic mice with cardiomyocyte-specific FOXO1 deletion had lower cardiac KLF5 expression and were protected from DbCM. Genetic, pharmacologic gain and loss of KLF5 function approaches and AAV-mediated Klf5 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 (NOX)4 promoter and induction of NOX4 expression. This was accompanied by accumulation of cardiac ceramides. Pharmacologic or genetic KLF5 inhibition alleviated superoxide formation, prevented ceramide accumulation and improved cardiac function in diabetic mice. Conclusions: Diabetes-mediated activation of cardiomyocyte FOXO1 increases KLF5 expression, which stimulates NOX4 expression, ceramide accumulation and causes DbCM.

Ketogenic Diet Suppressed T‐Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria‐Associated Membranes and Inhibiting Mitochondrial Function

“…In the cardiomyocytes, You et al found that KD contributes to the profibrotic actions in fibroblasts possibly via the mTOR signaling pathway in hypertension [6]. Besides, diabetes could modulate a wide range of cellular processes (e.g., autophagy, oxidative stress, and ferroptosis) in cardiomyocytes and endothelial cells, which could be important in the regulations of fibrosis during DCM development [45,46]. A lack of evidence on these aspects has restricted us to provide full information assessing the way that KD regulates DCM in vivo.…”

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

“…PPARα contributed to DiCM in this model by promoting triglyceride accumulation, resulting in a dysregulated oxidative stress status and mitochondrial dysfunction. Notably, Kyriazis et al recently reported PPARα-independent DiCM progression via molecular crosstalk between FOXO1 and KLF5 [148].…”

SFRP2 Improves Mitochondrial Dynamics and Mitochondrial Biogenesis, Oxidative Stress, and Apoptosis in Diabetic Cardiomyopathy

“…High glucose can cause oxidative stress and apoptosis of cardiomyocytes [6,29]. The utilization of glucose by 12 Oxidative Medicine and Cellular Longevity cardiomyocytes decreased in diabetes, which was conducive to the β-oxidation of free fatty acids (FFA).…”