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

2020 ◽  
Author(s):  
Ioannis Kyriazis ◽  
Matthew Hoffman ◽  
Lea Gaignebet ◽  
Anna Maria Lucchese ◽  
Eftychia Markopoulou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Cardiomyopathy ◽  
Major Complication ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Peroxisome Proliferator Activated Receptor ◽  
Patients With Diabetes ◽  
Ceramide Accumulation ◽  
Klf5 Expression

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.

Abstract 16563: FOXO1 Induces Cardiomyocyte-KLF5, Which Drives Oxidative Stress and Diabetic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ioannis D Kyriazis ◽  
Matthew K Hoffman ◽  
Lea Gaignebet ◽  
Anna Maria Lucchese ◽  
Chao Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Constitutive Expression ◽  
Diabetic Patients ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Lipid Species ◽  
Ceramide Accumulation ◽  
Klf5 Expression

Introduction: Cardiomyopathy in type 1 diabetes (T1D) is accompanied by impaired mitochondrial function, oxidative stress and lipotoxicity. We showed that cardiomyocyte (CM) Krüppel-like factor 5 (KLF5) is increased in streptozotocin-induced T1D and induces Peroxisome Proliferator Activated Receptor (PPAR)α in mice. Hypothesis: KLF5 upregulation by FOXO1 induces diabetic cardiomyopathy (DbCM). Methods and Results: Analyses in CM from diabetic patients showed higher KLF5 mRNA levels compared to non-diabetic individuals. In vitro mechanistic and in vivo analyses in αMHC- Foxo1 -/- mice revealed that FOXO1 stimulates KLF5 expression via direct promoter binding. Genetic inhibition of CM FOXO1 alleviated DbCM. Additionally, AAV-mediated CM-specific KLF5 overexpression in C57Bl/6 (WT) mice induced cardiac dysfunction. Mice with CM-specific KLF5 constitutive expression (αMHC-rtTA- Klf5 ), which we generated, recapitulated cardiomyopathy without T1D. Moreover, Pparα -/- mice with T1D, had higher CM-KLF5 levels and developed DbCM, suggesting that KLF5-driven DbCM is PPARα-independent. Additionally, CM-KLF5 induced oxidative stress through increased NADPH oxidase (NOX)4 expression and lower mitochondria abundance. Conversely, KLF5 inhibition prevented NOX4 upregulation and superoxide formation. Furthermore, CM-KLF5 promoted NOX4 expression via direct promoter binding. Antioxidant treatment in diabetic WT and αMHC-rtTA- Klf5 mice alleviated cardiac dysfunction partially, suggesting other pathways that contribute in KLF5-induced DbCM. For that, we performed cardiac lipidome analysis where we found clustering of αMHC-rtTA- Klf5 with diabetic WT mice. Of note, KLF5 inhibition in diabetic mice resulted in similar lipidome with non-diabetic WT mice. Individual lipid species analysis showed increased ceramide accumulation in diabetic WT and αMHC-rtTA- Klf5 mice that was reversed upon KLF5 inhibition. Thus, CM-KLF5 activation correlates with cardiac ceramide accumulation, that has been associated with cardiac lipotoxicity. Conclusions: In conclusion, T1D stimulates FOXO1, which induces CM-KLF5 expression that leads to oxidative stress and DbCM in a non-PPARα-dependent manner, as well as to cardiac ceramide accumulation.

Abstract P173: Caloric Restriction Attenuates Diabetic Cardiomyopathy Through the Recruitment of the Antioxidant System

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Maayan Waldman ◽  
Keren Cohen ◽  
Michael Arad ◽  
Nader G Abraham ◽  
Michal Laniado-Schwartzman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Caloric Restriction ◽  
Diabetic Cardiomyopathy ◽  
Diabetic Heart ◽  
Heart Weight ◽  
Internal Diameter ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Antioxidant Genes ◽  
Obesity And Diabetes

Introduction: Insulin resistance negatively impacts the diabetic heart in various ways, that include impaired insulin-mediated glucose uptake and a reduction in intracellular signalling. Diabetic cardiomyopathy is independent of coronary artery disease and is characterized by increased oxidative stress and extensive fibrotic changes, leading to increased myocardial stiffness and the development of diastolic dysfunction. Caloric restriction (CR) is cardioprotective mainly through its catabolic activity and increased insulin sensitivity. We examined the effect of CR on the development of diabetic cardiomyopathy and changes in oxidative stress and antioxidant genes. Methods: Leptin resistant (db/db) mice suffer from obesity and diabetes. Mice were treated for 4 weeks with angiotensin II (AT) to induce severe cardiomyopathy. Mice under CR were fed 90% of their normal food intake for 2 weeks and 65% for an additional 2 weeks. Each group consisted of 5-6 animals. Results: CR attenuated obesity and the cardiomyopathy phenotype in diabetic mice. CR reduced body weight and heart weight in diabetic mice when compared to control animals (33.7±7.9g vs.44 ±5.9g; 0.137±0.023g vs. 0.17±0.02g respectively, p<0.05); and lowered blood glucose (576±167mg/dL vs 702.5±309 mg/dL, p<0.05). Echocardiography indicated that CR attenuated the hypertrophic phenotype in the diabetic mice when compared to control animals (LV internal diameter 3.34±0.46mm vs. 4.06±0.36mm, p<0.01). Diabetic mice treated with AT suffer from oxidative stress as evident in a 110% increase in serum MDA levels (p<0.011), a reduction of 81% in adiponectin (p<0.001) and 65% in PGC-1α (p<0.0046) mRNA levels in cardiac tissue of diabetic mice compared to WT mice. The attenuation of diabetic cardiomyopathy after CR was accompanied by a reduction in serum MDA levels (p<0.028) and an increase in cardiac adiponectin, HO-1 and PGC-1α levels (p<0.05). Conclusion: These results indicate that a short term CR attenuated the development of AT induced diabetic cardiomyopathy through the activation of the adiponectin- PGC-1α- HO-1-axis. This appears to be a critical module in protecting the diabetic heart from the development of cardiomyopathy.

Natural Aldose Reductase Inhibitor: A Potential Therapeutic Agent for Non-alcoholic Fatty Liver Disease

2020 ◽  
Vol 21 (6) ◽  
pp. 599-609 ◽  
Author(s):  
Longxin Qiu ◽  
Chang Guo
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Aldose Reductase ◽  
Fatty Liver Disease ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver

Aldose reductase (AR) has been reported to be involved in the development of nonalcoholic fatty liver disease (NAFLD). Hepatic AR is induced under hyperglycemia condition and converts excess glucose to lipogenic fructose, which contributes in part to the accumulation of fat in the liver cells of diabetes rodents. In addition, the hyperglycemia-induced AR or nutrition-induced AR causes suppression of the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) α and reduced lipolysis in the liver, which also contribute to the development of NAFLD. Moreover, AR induction in non-alcoholic steatohepatitis (NASH) may aggravate oxidative stress and the expression of inflammatory cytokines in the liver. Here, we summarize the knowledge on AR inhibitors of plant origin and review the effect of some plant-derived AR inhibitors on NAFLD/NASH in rodents. Natural AR inhibitors may improve NAFLD at least in part through attenuating oxidative stress and inflammatory cytokine expression. Some of the natural AR inhibitors have been reported to attenuate hepatic steatosis through the regulation of PPARα-mediated fatty acid oxidation. In this review, we propose that the natural AR inhibitors are potential therapeutic agents for NAFLD.

scholarly journals Lack of association between peroxisome proliferator-activated receptor-gamma-2 gene variants and the occurrence of coronary heart disease in patients with diabetes mellitus

2002 ◽  
pp. 545-551 ◽  
Author(s):  
M Bluher ◽  
T Klemm ◽  
T Gerike ◽  
H Krankenberg ◽  
G Schuler ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Multiple Logistic Regression Analysis ◽  
Peroxisome Proliferator ◽  
Haemoglobin A1c ◽  
Peroxisome Proliferator Activated Receptor ◽  
Patients With Diabetes ◽  
Reduced Risk

OBJECTIVE: Recent evidence indicates that peroxisome proliferator-activated receptor-gamma (PPARgamma) is expressed at high levels in foam cells of atherosclerotic lesions, that PPARgamma agonists may directly modulate vessel wall function and that mutations in the PPARgamma-2 gene are associated with a reduced risk of coronary artery disease. METHODS: We investigated whether known variants in the PPARgamma-2 gene are associated with the occurrence of coronary heart disease (CHD) in 365 patients with type 2 diabetes, prospectively characterised for the presence or absence of CHD. The Pro115Gln, Pro12Ala, Pro467Leu, Val290Met mutations and two polymorphisms C478T and C161T of the PPARgamma-2 gene were examined using PCR, denaturing gradient gel electrophoresis and direct sequencing. RESULTS: The distribution of the Pro12Ala, Ala12Ala, C161T and T161T variants was not significantly different between patients with and without CHD, independent of the gender. The Pro12Ala (P=0.011) and the Ala12Ala (P=0.006) variant were associated with a higher body mass index (BMI) compared with the Pro12Pro genotype. A multiple logistic regression analysis introducing the typical risk factors for CHD (age, sex, hypertension, smoking, BMI >26 kg/m2, elevated low density lipoprotein cholesterol and haemoglobin A1c >7%) identified age >60, male gender, hypertension and a higher BMI, but not the PPARgamma-2 variants, as significant risk factors for CHD in our study groups. CONCLUSION: The PPARgamma-2 genotype was not associated with an increased or reduced risk of the occurrence of CHD and can therefore not be regarded as an independent risk factor for CHD in patients with diabetes mellitus.

Thyroid hormone is required for the phenotype transitions induced by the pharmacological inhibition of calcineurin in adult soleus muscle of rats

2008 ◽  
Vol 294 (1) ◽  
pp. E69-E77 ◽  
Author(s):  
Nathalie Koulmann ◽  
Lahoucine Bahi ◽  
Florence Ribera ◽  
Hervé Sanchez ◽  
Bernard Serrurier ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Soleus Muscle ◽  
Hormone Deficiency ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Thyroid State ◽  
Novel Approach ◽  
A Subunit ◽  
Calcineurin Inhibition

The present experiment was designed to examine the effects of hypothyroidism and calcineurin inhibition induced by cyclosporin A (CsA) administration on both contractile and metabolic soleus muscle phenotypes, with a novel approach to the signaling pathway controlling mitochondrial biogenesis. Twenty-eight rats were randomly assigned to four groups, normothyroid, hypothyroid, and orally treated with either CsA (25 mg/kg, N-CsA and H-CsA) or vehicle (N-Vh and H-Vh), for 3 wk. Muscle phenotype was estimated by the MHC profile and activities of oxidative and glycolytic enzymes. We measured mRNA levels of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), the major regulator of mitochondrial content. We also studied the expression of the catalytic A-subunit of calcineurin (CnA) both at protein and transcript levels and mRNA levels of modulatory calcineurin inhibitor proteins (MCIP)-1 and -2, which are differentially regulated by calcineurin activity and thyroid hormone, respectively. CsA-administration induced a slow-to-fast MHC transition limited to the type IIA isoform, which is associated with increased oxidative capacities. Hypothyroidism strongly decreased both the expression of fast MHC isoforms and oxidative capacities. Effects of CsA administration on muscle phenotype were blocked in conditions of thyroid hormone deficiency. Changes in the oxidative profile were strongly related to PGC-1α changes and associated with phosphorylation of p38 MAPK. Calcineurin and MCIPs mRNA levels were decreased by both hypothyroidism and CsA without additive effects. Taken together, these results suggest that adult muscle phenotype is primarily under the control of thyroid state. Physiological levels of thyroid hormone are required for the effects of calcineurin inhibition on slow oxidative muscle phenotype.

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