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

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.

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

Circulation Research ◽

10.1161/circresaha.120.316738 ◽

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.

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Therapeutic effect of MG-132 on diabetic cardiomyopathy is associated with its suppression of proteasomal activities: roles of Nrf2 and NF-κB

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00650.2012 ◽

2013 ◽

Vol 304 (4) ◽

pp. H567-H578 ◽

Cited By ~ 57

Author(s):

Yuehui Wang ◽

Weixia Sun ◽

Bing Du ◽

Xiao Miao ◽

Yang Bai ◽

...

Keyword(s):

Therapeutic Effect ◽

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Left Ventricular ◽

Nuclear Accumulation ◽

Left Ventricular Ejection ◽

Heart Weight ◽

Diabetic Mice ◽

Antioxidant Genes ◽

Antioxidative Function

MG-132, a proteasome inhibitor, can upregulate nuclear factor (NF) erythroid 2-related factor 2 (Nrf2)-mediated antioxidative function and downregulate NF-κB-mediated inflammation. The present study investigated whether through the above two mechanisms MG-132 could provide a therapeutic effect on diabetic cardiomyopathy in the OVE26 type 1 diabetic mouse model. OVE26 mice develop hyperglycemia at 2–3 wk after birth and exhibit albuminuria and cardiac dysfunction at 3 mo of age. Therefore, 3-mo-old OVE26 diabetic and age-matched control mice were intraperitoneally treated with MG-132 at 10 μg/kg daily for 3 mo. Before and after MG-132 treatment, cardiac function was measured by echocardiography, and cardiac tissues were then subjected to pathological and biochemical examination. Diabetic mice showed significant cardiac dysfunction, including increased left ventricular systolic diameter and wall thickness and decreased left ventricular ejection fraction with an increase of the heart weight-to-tibia length ratio. Diabetic hearts exhibited structural derangement and remodeling (fibrosis and hypertrophy). In diabetic mice, there was also increased systemic and cardiac oxidative damage and inflammation. All of these pathogenic changes were reversed by MG-132 treatment. MG-132 treatment significantly increased the cardiac expression of Nrf2 and its downstream antioxidant genes with a significant increase of total antioxidant capacity and also significantly decreased the expression of IκB and the nuclear accumulation and DNA-binding activity of NF-κB in the heart. These results suggest that MG-132 has a therapeutic effect on diabetic cardiomyopathy in OVE26 diabetic mice, possibly through the upregulation of Nrf2-dependent antioxidative function and downregulation of NF-κB-mediated inflammation.

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Abstract 11989: Cardiac 12-Lipoxygenase-Induced Oxidative Stress Promotes the Development of Diabetic Cardiomyopathy

Circulation ◽

10.1161/circ.130.suppl_2.11989 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Yosuke Kayama ◽

Hirofumi Suzuki ◽

Masaya Sakamoto ◽

Ippei Shimizu ◽

Tomohisa Nagoshi ◽

...

Keyword(s):

Oxidative Stress ◽

Membrane Potential ◽

Diabetic Cardiomyopathy ◽

Mitochondrial Membrane ◽

Cardiac Fibrosis ◽

Diabetic Heart ◽

Diabetic Mice ◽

12 Lipoxygenase ◽

Glucose Condition

Diabetes mellitus affects cardiac structure and function, and it has been suggested that diabetes leads to cardiomyopathy. Arachidonic acid (AA) metabolism was thought to be a potential mediator of cardiac fibrosis and heart failure associated with oxidative stress. 12-lipoxygenase (12-LOX) is a key lipid peroxidizing enzyme of the AA cascade that plays an important role in the development of atherogenesis and neurodegenerative disease. However, the role of 12-LOX in diabetic cardiomyopathy has not been examined. To determine whether 12-LOX is a key molecule in the development of diabetic cardiomyopathy, we created streptozotocin (STZ)-induced diabetic mice (WT-STZ) and compared to control mice. Cardiac expression of 12-LOX pathway was up-regulated after induction of diabetes. Histological analysis revealed that expression of 12-LOX was specifically up-regulated in cardiomyocytes but not vascular cells and fibroblast cells. Cardiac fibrosis was increased after induction of diabetes. We next created STZ-induced diabetic mice using 12-LOX KO mice (KO-STZ) and compared them to WT-STZ. Cardiac dysfunction and fibrosis in WT-STZ were significantly inhibited in KO-STZ. We next examined the relationship between 12-LOX and cardiac oxidative stress in the diabetic heart. Cardiac expression of 4-hydroxy-2-nonenal (4-HNE) and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) were up-regulated in the diabetic heart. This increase was inhibited by disruption of 12-LOX. To further investigate the subcellular mechanism of the increase reactive oxygen species (ROS) in the diabetic heart, intracellular ROS levels in cardiomyocytes were estimated under high glucose condition (HG) and normal glucose condition (LG) by fluorimetry and using MitoTracker® Red in vitro. Cardiomyocytes under HG showed the enhancement of fluorescence intensity of DCF-DA and loss of mitochondrial membrane potential. Treatment with 12-LOX inhibitor (CDC) improved the enhancement of DCF-DA and mitochondrial membrane potential under HG condition. These in vivo and in vitro results suggest that 12-LOX pathway is important in the process of production of ROS and oxidative stress in diabetic heart and promotes the development of diabetic cardiomyopathy.

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ARNT Mediates Chemotherapy Resistance by Modulating the Response to Oxidative Stress in AML Cells.

Blood ◽

10.1182/blood.v114.22.2737.2737 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2737-2737

Author(s):

Richard A. Wells ◽

Chunhong Gu ◽

Joelle dela Paz

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Cell Lines ◽

Akt Signaling ◽

Mrna Levels ◽

Antioxidant Genes ◽

Protein Levels ◽

Exogenous Expression ◽

Induction Of Apoptosis ◽

Induced Apoptosis

Abstract Abstract 2737 Poster Board II-713 Background Although patients with acute myelogenous leukaemia (AML) typically respond well to initial therapy, with over 75% of patients achieving complete remission, in the great majority the disease ultimately relapses. This is thought to be due to the inherent resistance of leukaemia stem cells to the effects of chemotherapy. While some mechanisms of chemoresistance, e.g. TP53 mutation and upregulation of P-glycoprotein expression, have been well characterized, this phenomenon remains incompletely understood and is a significant barrier to improving patient outcomes. Methods and results The thiazolidindione drug troglitazone (TG) induces apoptosis in AML cells via generation of intracellular reactive oxygen species (ROS), but the degree of sensitivity to TG is highly heterogeneous among AML cell lines. We studied expression of the transcription factor ARNT (aryl hydrocarbon nuclear translocator) in TG-sensitive and TG-resistant AML cell lines following TG treatment. In HL-60 cells, which are highly sensitive to induction of apoptosis by TG, ARNT mRNA levels remained constant following TG treatment and ARNT protein levels markedly decreased, while in U937 cells, which are TG resistant, ARNT mRNA levels increased and ARNT protein levels remained constant. We then tested the effect of exogenous expression of ARNT on the sensitivity of HL-60 cells to TG-induced apoptosis. HL-60 cells transduced with a retrovirus expressing ARNT became TG-resistant. Exogenous expression of ARNT also conferred resistance to induction of apoptosis by hydrogen peroxide, daunorubicin and etoposide. The cellular response to oxidative stress is governed by intracellular signaling pathways and through a transcriptional response through which expression of antioxidant genes is coordinated. HL-60 cells expressing ARNT had striking constitutive activation of AKT signaling, and treatment of these cells with a specific inhibitor of AKT signaling reversed their resistance to TG-induced apoptosis. The activation of AKT signaling by ARNT appears to be mediated by downregulation of expression of PP2A and alpha4, two key negative regulators of AKT phosphorylation. In addition, ARNT-transduced HL-60 cells showed increased expression of Nrf2, a key transcriptional regulator of the antioxidant response, and its target genes SOD2 and CAT. Conclusions The response to oxidative stress is heterogeneous in AML cells lines, and varies with expression of ARNT. ARNT activates expression of Nrf2, which stimulates expression of antioxidant genes resulting in an augmented adaptive response to ROS. Unexpectedly, ARNT also activates AKT signaling by repressing expression of the regulatory phosphatases PP2A and alpha4. These activities of ARNT result in increased resistance to the induction of apoptosis by TG, hydrogen peroxide, and chemotherapy. ARNT may play an important role in chemoresistance in and may be useful as a predictive or prognostic biomarker. Disclosures: No relevant conflicts of interest to declare.

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Ameliorative Effect of Hexane Extract ofPhalaris canariensison High Fat Diet-Induced Obese and Streptozotocin-Induced Diabetic Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/145901 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 8

Author(s):

Rosa Martha Perez Gutierrez ◽

Diana Madrigales Ahuatzi ◽

Maria del Carmen Horcacitas ◽

Efren Garcia Baez ◽

Teresa Cruz Victoria ◽

...

Keyword(s):

Oxidative Stress ◽

Body Weight ◽

High Fat Diet ◽

Serum Insulin ◽

Body Weight Loss ◽

Insulin Level ◽

Hexane Extract ◽

Diabetic Mice ◽

High Fat ◽

Obesity And Diabetes

Obesity is one of the major factors to increase various disorders like diabetes. The present paper emphasizes study related to the antiobesity effect ofPhalaris canariensisseeds hexane extract (Al-H) in high-fat diet- (HFD-) induced obese CD1 mice and in streptozotocin-induced mild diabetic (MD) and severely diabetic (SD) mice.AL-H was orally administered to MD and SD mice at a dose of 400 mg/kg once a day for 30 days, and a set of biochemical parameters were studied: glucose, cholesterol, triglycerides, lipid peroxidation, liver and muscle glycogen, ALP, SGOT, SGPT, glucose-6-phosphatase, glucokinase, hexokinase, SOD, CAT, GSH, GPX activities, and the effect on insulin level. HS-H significantly reduced the intake of food and water and body weight loss as well as levels of blood glucose, serum cholesterol, triglyceride, lipoprotein, oxidative stress, showed a protective hepatic effect, and increased HDL-cholesterol, serum insulin in diabetic mice. The mice fed on the high-fat diet and treated with AL-H showed inhibitory activity on the lipid metabolism decreasing body weight and weight of the liver and visceral adipose tissues and cholesterol and triglycerides in the liver. We conclude that AL-H can efficiently reduce serum glucose and inhibit insulin resistance, lipid abnormalities, and oxidative stress in MD and SD mice. Our results demonstrate an antiobesity effect reducing lipid droplet accumulation in the liver, indicating that its therapeutic properties may be due to the interaction plant components soluble in the hexane extract, with any of the multiple targets involved in obesity and diabetes pathogenesis.

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The Role of Heme Oxygenase 1 in the Protective Effect of Caloric Restriction against Diabetic Cardiomyopathy

International Journal of Molecular Sciences ◽

10.3390/ijms20102427 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2427 ◽

Cited By ~ 8

Author(s):

Maayan Waldman ◽

Vadim Nudelman ◽

Asher Shainberg ◽

Romy Zemel ◽

Ran Kornwoski ◽

...

Keyword(s):

Oxidative Stress ◽

Beneficial Effect ◽

Heme Oxygenase ◽

Diabetic Cardiomyopathy ◽

High Glucose ◽

Heme Oxygenase 1 ◽

Ros Production ◽

Diabetic Mice ◽

Protein Levels

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1–PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. Methods: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5–33 mM). We examined the effects of Sn(tin)-mesoporphyrin (SnMP), which is an inhibitor of HO activity, the HO-1 inducer cobalt protoporphyrin (CoPP), and the SIRT1 inhibitor (EX-527) on diabetic cardiomyopathy. Results: Diabetic mice had low levels of HO-1 and elevated levels of the oxidative marker malondialdehyde (MDA). CR attenuated left ventricular hypertrophy (LVH), increased HO-1 levels, and decreased MDA levels. SnMP abolished the protective effects of CR and caused pronounced LVH and cardiac metabolic dysfunction represented by suppressed levels of adiponectin, SIRT1, PPARγ, PGC-1α, and increased MDA. High glucose (33 mM) increased ROS in cultured cardiomyocytes, while SnMP reduced SIRT1, PGC-1α levels, and HO activity. Similarly, SIRT1 inhibition led to a reduction in PGC-1α and HO-1 levels. CoPP increased HO-1 protein levels and activity, SIRT1, and PGC-1α levels, and decreased ROS production, suggesting a positive feedback between SIRT1 and HO-1. Conclusion: These results establish a link between SIRT1, PGC-1α, and HO-1 signaling that leads to the attenuation of ROS production and diabetic cardiomyopathy. CoPP mimicked the beneficial effect of CR, while SnMP increased oxidative stress, aggravating cardiac hypertrophy. The data suggest that increasing HO-1 levels constitutes a novel therapeutic approach to protect the diabetic heart. Brief Summary: CR attenuates cardiomyopathy, and increases HO-1, SIRT activity, and PGC-1α protein levels in diabetic mice. High glucose reduces adiponectin, SIRT1, PGC1-1α, and HO-1 levels in cardiomyocytes, resulting in oxidative stress. The pharmacological activation of HO-1 activity mimics the effect of CR, while SnMP increased oxidative stress and cardiac hypertrophy. These data suggest the critical role of HO-1 in protecting the diabetic heart.

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Prevention by Dietary Polyphenols (Resveratrol, Quercetin, Apigenin) Against 7-Ketocholesterol-Induced Oxiapoptophagy in Neuronal N2a Cells: Potential Interest for the Treatment of Neurodegenerative and Age-Related Diseases

Cells ◽

10.3390/cells9112346 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2346

Author(s):

Aline Yammine ◽

Amira Zarrouk ◽

Thomas Nury ◽

Anne Vejux ◽

Norbert Latruffe ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Expression Level ◽

Cholesterol Oxidation ◽

Mrna Levels ◽

Antioxidant Genes ◽

Dietary Polyphenols ◽

N2a Cells ◽

Age Related ◽

The Impact

The Mediterranean diet is associated with health benefits due to bioactive compounds such as polyphenols. The biological activities of three polyphenols (quercetin (QCT), resveratrol (RSV), apigenin (API)) were evaluated in mouse neuronal N2a cells in the presence of 7-ketocholesterol (7KC), a major cholesterol oxidation product increased in patients with age-related diseases, including neurodegenerative disorders. In N2a cells, 7KC (50 µM; 48 h) induces cytotoxic effects characterized by an induction of cell death. When associated with RSV, QCT and API (3.125; 6.25 µM), 7KC-induced toxicity was reduced. The ability of QCT, RSV and API to prevent 7KC-induced oxidative stress was characterized by a decrease in reactive oxygen species (ROS) production in whole cells and at the mitochondrial level; by an attenuation of the increase in the level and activity of catalase; by attenuating the decrease in the expression, level and activity of glutathione peroxidase 1 (GPx1); by normalizing the expression, level and activity of superoxide dismutases 1 and 2 (SOD1, SOD2); and by reducing the decrease in the expression of nuclear erythroid 2-like factor 2 (Nrf2) which regulates antioxidant genes. QCT, RSV and API also prevented mitochondrial dysfunction in 7KC-treated cells by counteracting the loss of mitochondrial membrane potential (ΨΔm) and attenuating the decreased gene expression and/or protein level of AMP-activated protein kinase α (AMPKα), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) implicated in mitochondrial biogenesis. At the peroxisomal level, QCT, RSV and API prevented the impact of 7KC by counteracting the decrease in ATP binding cassette subfamily D member (ABCD)3 (a peroxisomal mass marker) at the protein and mRNA levels, as well as the decreased expresssion of genes associated with peroxisomal biogenesis (Pex13, Pex14) and peroxisomal β-oxidation (Abcd1, Acox1, Mfp2, Thiolase A). The 7KC-induced decrease in ABCD1 and multifunctional enzyme type 2 (MFP2), two proteins involved in peroxisomal β-oxidation, was also attenuated by RSV, QCT and API. 7KC-induced cell death, which has characteristics of apoptosis (cells with fragmented and/or condensed nuclei; cleaved caspase-3; Poly(ADP-ribose) polymerase (PARP) fragmentation) and autophagy (cells with monodansyl cadaverine positive vacuoles; activation of microtubule associated protein 1 light chain 3–I (LC3-I) to LC3-II, was also strongly attenuated by RSV, QCT and API. Thus, in N2a cells, 7KC induces a mode of cell death by oxiapoptophagy, including criteria of OXIdative stress, APOPTOsis and autoPHAGY, associated with mitochondrial and peroxisomal dysfunction, which is counteracted by RSV, QCT, and API reinforcing the interest for these polyphenols in prevention of diseases associated with increased 7KC levels.

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LCZ696, an angiotensin receptor-neprilysin inhibitor, ameliorates diabetic cardiomyopathy by inhibiting inflammation, oxidative stress and apoptosis

Experimental Biology and Medicine ◽

10.1177/1535370219861283 ◽

2019 ◽

Vol 244 (12) ◽

pp. 1028-1039 ◽

Cited By ~ 2

Author(s):

Qing Ge ◽

Li Zhao ◽

Xiao-Min Ren ◽

Peng Ye ◽

Zuo-Ying Hu

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Diabetic Cardiomyopathy ◽

Ventricular Remodeling ◽

Heart Tissue ◽

Inflammatory Factors ◽

Diabetic Mice ◽

Angiotensin Receptor ◽

Neprilysin Inhibitor ◽

Angiotensin Receptor Neprilysin Inhibitor

Diabetic cardiomyopathy, which refers to the destruction of the structure and function of the heart, is the primary cause of heart failure due to diabetes. LCZ696 is the first angiotensin receptor-neprilysin inhibitor (ARNi) to be used clinically. Our study investigated the role played by LCZ696 during diabetic cardiomyopathy and explored the potential mechanisms underlying these effects. Diabetes was induced by injecting streptozotocin intraperitoneally into mice, and the mice were then divided randomly into two groups: one group was treated with LCZ696 (60 mg/kg/d) for 16 weeks, and the other received no treatment. The H9C2 cardiomyoblast cell line was treated with LCZ696 under high-glucose (HG) conditions. The levels of apoptotic (Bax, Bcl-2 and cleaved caspase-3) and pro-inflammatory factors [nuclear factor (NF)-κB, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase (MAPK)] were assessed in heart tissues from diabetic and normal mice and in H9C2 cells. The heart tissue structures and cardiac functions of diabetic mice were compared with those of normal mice, using histological and echocardiographic analyses. The results showed that LCZ696 inhibits the nuclear transfer of NF-κB and JNK/p38MAPK phosphorylation, and mitigates inflammation and apoptosis in diabetic mice and H9C2 cardiomyocytes under HG conditions. The histological and echocardiographic data showed that compared with untreated diabetic mice, diabetic mice treated with LCZ696 exhibited improved ventricular remodeling and cardiac function. LCZ696 also ameliorated oxidative stress in both vivo and vitro. In conclusion, LCZ696 improved diabetic cardiomyopathy by reducing cardiac inflammation, oxidative stress, and apoptosis. Impact statement Diabetic cardiomyopathy (DCM) is an important cause of heart failure in patients with diabetes, resulting in increased morbidity and mortality. LCZ696, which was studied here, is a novel drug for the treatment of heart failure. The latest research reports that LCZ696 is more effective for preventing heart failure than valsartan alone. However, little research has been performed examining the effects of LCZ696 on DCM. This study was designed to examine the role played by LCZ696 during DCM and the potential mechanisms underlying these effects, which may provide the basis for a new therapeutic strategy for DCM.

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Simvastatin Ameliorates Diabetic Cardiomyopathy by Attenuating Oxidative Stress and Inflammation in Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/1092015 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 21

Author(s):

Nawal M. Al-Rasheed ◽

Nouf M. Al-Rasheed ◽

Iman H. Hasan ◽

Maha A. Al-Amin ◽

Hanaa N. Al-Ajmi ◽

...

Keyword(s):

Oxidative Stress ◽

Body Weight ◽

Diabetic Cardiomyopathy ◽

Troponin I ◽

Body Weight Loss ◽

Diabetic Rats ◽

Antioxidant Defenses ◽

Lipid Lowering ◽

Diabetic Heart ◽

Creatine Kinase Mb

Simvastatin is a lipid-lowering agent used to treat hypercholesterolemia and to reduce the risk of heart disease. This study scrutinized the beneficial effects of simvastatin on experimental diabetic cardiomyopathy (DCM), pointing to the role of hyperglycemia-induced oxidative stress and inflammation. Diabetes was induced by intraperitoneal injection of streptozotocin and both control and diabetic rats received simvastatin for 90 days. Diabetic rats showed significant cardiac hypertrophy, body weight loss, hyperglycemia, and hyperlipidemia. Serum creatine kinase MB (CK-MB) and troponin I showed a significant increase in diabetic rats. Simvastatin significantly improved body weight, attenuated hyperglycemia and hyperlipidemia, and ameliorated CK-MB and troponin I. Simvastatin prevented histological alterations and deposition of collagen in the heart of diabetic animals. Lipid peroxidation and nitric oxide were increased in the heart of diabetic rats whereas antioxidant defenses were decreased. These alterations were significantly reversed by simvastatin. In addition, simvastatin decreased serum inflammatory mediators and expression of NF-κB in the diabetic heart. Cardiac caspase-3 was increased in the diabetic heart and decreased following treatment with simvastatin. In conclusion, our results suggest that simvastatin alleviates DCM by attenuating hyperglycemia/hyperlipidemia-induced oxidative stress, inflammation, and apoptosis.

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Dahuang Danshen Decoction Inhibits Pancreatic Fibrosis by Regulating Oxidative Stress and Endoplasmic Reticulum Stress

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6629729 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Xiaoqiang Liang ◽

Mian Han ◽

Xuelin Zhang ◽

Xun Sun ◽

Kui Yu ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Molecular Docking ◽

Endoplasmic Reticulum Stress ◽

Serum Levels ◽

Pancreatic Fibrosis ◽

Mrna Levels ◽

Antioxidant Genes ◽

Caspase 12

Background. In Traditional Chinese Medicine (TCM), Dahuang Danshen decoction (DD) is used to treat pancreatic fibrosis. Pancreatic fibrosis is a typical manifestation of chronic pancreatitis (CP), which affects the digestive system. The therapeutic mechanisms of DD in pancreatic fibrosis are unclear. Aim. This study aimed to investigate the regulatory mechanisms of DD on oxidative stress and endoplasmic reticulum stress in CP. Materials and Methods. Experimental rats were intraperitoneally injected with 500 mg/kg BW of diethyldithiocarbamate (DDC) twice a week for six weeks to induce CP. At the same time, DD was administered orally at daily doses of 1.37 g/kg BW, 2.74 g/kg BW, and 5.48 g/kg BW to evaluate its treatment effects on CP. After all treatments, pancreatic tissues were harvested and subjected to H&E staining. Transmission electron microscopy (TEM) was also performed to show the endoplasmic reticulum structure in the pancreatic tissues. Immunohistochemistry was used to detect the α-SMA expression level in the pancreatic tissues. Metabolomics analysis of the serum and proteomics analysis of the pancreatic tissues were performed to reveal the changes of endogenous metabolites and proteins, respectively. Concentrations of GSH, MDA, SOD, ROS, col-1, and col-3 were determined using corresponding kits. The western blotting method was used to determine the protein levels of Keap-1, HO-1, NQO1, Nrf2, GRP, JNK, and caspase 12. The pancreatic mRNA levels of NQO1, GPX1, HO-1, GST-π, GRP, JNK, and caspase 12 were also determined by quantitative PCR. The interactions between TCM components and Keap-1 were investigated by molecular docking modeling. Results. The pathohistological results demonstrated that DD could ameliorate DDC-induced CP in vivo, indicated by reduction of α-SMA, col-1, col-3, TNF-α, and IL-6. DD increased serum levels of GSH and SOD but reduced pancreatic ROS. DD decreased cytoplasmic Keap-1 and increased Nrf2 nuclear localization. Correspondingly, DD increased the expression levels of Nrf2 downstream antioxidant genes NQO1, GPX1, HO-1, and GST-π. DD also decreased ERS hallmarks caspase 12 cleavage and GRP expression. Eventually, DD inhibited PSC activation by reducing JNK phosphorylation and MMK-3/p38 expression. Molecular docking analysis showed that salvianolic acid B and emodin had a good binding affinity toward Keap-1. Conclusions. These results demonstrated that DD could ameliorate the oxidative and endoplasmic reticulum stress through releasing Nrf2 from Keap-1 binding and inducing the downstream antioxidant enzymes. As a result, DD could thwart pancreatic fibrosis by inhibiting PSCs activation, which was induced by OS and ERS through JNK and MMK3/p38 pathways.

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