Angiotensin receptor-mediated oxidative stress is associated with impaired cardiac redox signaling and mitochondrial function in insulin-resistant rats

Activation of angiotensin receptor type 1 (AT1) contributes to NADPH oxidase (Nox)-derived oxidative stress during metabolic syndrome. However, the specific role of AT1 in modulating redox signaling, mitochondrial function, and oxidative stress in the heart remains more elusive. To test the hypothesis that AT1 activation increases oxidative stress while impairing redox signaling and mitochondrial function in the heart during diet-induced insulin resistance in obese animals, Otsuka Long Evans Tokushima Fatty (OLETF) rats ( n = 8/group) were treated with the AT1 blocker (ARB) olmesartan for 6 wk. Cardiac Nox2 protein expression increased 40% in OLETF compared with age-matched, lean, strain-control Long Evans Tokushima Otsuka (LETO) rats, while mRNA and protein expression of the H2O2-producing Nox4 increased 40–100%. ARB treatment prevented the increase in Nox2 without altering Nox4. ARB treatment also normalized the increased levels of protein and lipid oxidation (nitrotyrosine, 4-hydroxynonenal) and increased the redox-sensitive transcription factor Nrf2 by 30% and the activity of antioxidant enzymes (SOD, catalase, GPx) by 50–70%. Citrate synthase (CS) and succinate dehydrogenase (SDH) activities decreased 60–70%, whereas cardiac succinate levels decreased 35% in OLETF compared with LETO, suggesting that mitochondrial function in the heart is impaired during obesity-induced insulin resistance. ARB treatment normalized CS and SDH activities, as well as succinate levels, while increasing AMPK and normalizing Akt, suggesting that AT1 activation also impairs cellular metabolism in the diabetic heart. These data suggest that the cardiovascular complications associated with metabolic syndrome may result from AT1 receptor-mediated Nox2 activation leading to impaired redox signaling, mitochondrial activity, and dysregulation of cellular metabolism in the heart.

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Abstract 623: Angiotensin Receptor Activation Contributes to Glucose Intolerance and Increased Insulin Resistance Independent of Elevated Systolic Blood Pressure, Adiposity and Dyslipidemia in a Model of Metabolic Syndrome

Hypertension ◽

10.1161/hyp.62.suppl_1.a623 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Andrew Y Lee ◽

Ruben R Rodriguez ◽

Bridget Martinez ◽

Daisuke Nakano ◽

Akira Nishiyama ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Metabolic Syndrome ◽

Glucose Tolerance ◽

Systolic Blood Pressure ◽

Body Mass ◽

Elevated Blood ◽

Angiotensin Receptor ◽

Plasma Triglycerides ◽

Long Evans

Activation of the renin-angiotensin system (RAS) leads to an increase in blood pressure and onset of insulin resistance (IR); however, the contributions of increased blood pressure and AT1 activation independently on the manifestation of IR are not well defined. The goal of this study was to determine the contribution of elevated blood pressure, independent of RAS, to the onset of IR in a model of metabolic syndrome. To address the hypothesis that AT1 activation, and not elevated blood pressure independently, is the principal contributor of obesity-associated IR, we measured changes in systolic blood pressure (SBP), adiposity, plasma triglycerides (TG), glucose tolerance, and insulin resistance index (IRI) in four groups of rats: 1) lean strain-control Long Evans Tokushima Otsuka (LETO; n=5), 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF; n=7), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg; n=8), and 4) OLETF + calcium channel blocker (CCB; 5 mg amlodipine/kg; n=7). ARB treatment alleviated the obesity-related increase in mean SBP, while the decrease with CCB remained 10.2 mmHg greater than LETO. ARB (0.51 g/100g body mass) and CCB (0.64 g/100g body mass) reduced mean relative retroperitoneal fat mass and mean plasma triglycerides (28.4 and 27.4 mg/dL respectively) compared to OLETF, but both remained greater (1.7, 1.57 g/100g body mass and 28.94, 29.94 mg/dL respectively) than LETO. ARB improved glucose tolerance by 4605.94 of 34965.94 and mean calculated IRI by 5581429.5 of 17398363, but CCB had no detectable effect on either. Despite relatively similar reductions in SBP, adiposity and plasma TG (principal components of metabolic syndrome), CCB did not improve glucose tolerance and IRI (additional metrics of metabolic syndrome), while ARB did, demonstrating that AT1 activation is the primary factor contributing to the development of impaired glucose metabolism and regulation during metabolic syndrome, independent of the hypertension, adiposity and dyslipidemia. Thus, targeting RAS to improve the consequences of metabolic syndrome appears to be prudent and effective.

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Angiotensin Receptor Blockade Reduces Oxidative Stress while Improving Redox Signaling and Mitochondrial Function in the Heart of Diet‐induced Obese Insulin Resistant Rats

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.918.3 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Jose Pablo Vazquez‐Medina ◽

Irina Popovich ◽

Max A Thorwald ◽

Ruben Rodriguez ◽

Jose A Viscarra ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Function ◽

Redox Signaling ◽

Receptor Blockade ◽

Angiotensin Receptor ◽

Insulin Resistant ◽

Angiotensin Receptor Blockade

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Oxidative stress and metabolic syndrome: Effects of a natural antioxidants enriched diet on insulin resistance

Clinical Nutrition ESPEN ◽

10.1016/j.clnesp.2014.11.002 ◽

2015 ◽

Vol 10 (2) ◽

pp. e52-e60 ◽

Cited By ~ 7

Author(s):

Antonio Mancini ◽

Giuseppe Ettore Martorana ◽

Marinella Magini ◽

Roberto Festa ◽

Sebastiano Raimondo ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Natural Antioxidants

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Oxidative Stress and Metabolic Syndrome: Effects of Natural Dietary Antioxidants in Obese Patients with Insulin Resistance.

10.1210/endo-meetings.2010.part3.p9.p3-428 ◽

2010 ◽

pp. P3-428-P3-428

Author(s):

A Mancini ◽

GE Martorana ◽

V Di Donna ◽

E Leone ◽

S Raimondo ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Obese Patients ◽

Dietary Antioxidants

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The renin angiotensin system, oxidative stress and mitochondrial function in obesity and insulin resistance

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2016.07.019 ◽

2017 ◽

Vol 1863 (5) ◽

pp. 1106-1114 ◽

Cited By ~ 77

Author(s):

Latha Ramalingam ◽

Kalhara Menikdiwela ◽

Monique LeMieux ◽

Jannette M. Dufour ◽

Gurvinder Kaur ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Mitochondrial Function ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin

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Homocysteine is the confounding factor of metabolic syndrome-confirmed by siMS score

Drug Metabolism and Personalized Therapy ◽

10.1515/dmpt-2017-0013 ◽

2018 ◽

Vol 33 (2) ◽

pp. 99-103 ◽

Cited By ~ 2

Author(s):

Branko Srećković ◽

Ivan Soldatovic ◽

Emina Colak ◽

Igor Mrdovic ◽

Mirjana Sumarac-Dumanovic ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Risk Score ◽

Continuous Measure ◽

Model Assessment ◽

Anthropometric Parameters ◽

Apo B ◽

Significant Difference ◽

Homeostatic Model Assessment

Abstract Background: Abdominal adiposity has a central role in developing insulin resistance (IR) by releasing pro-inflammatory cytokines. Patients with metabolic syndrome (MS) have higher values of homocysteine. Hyperhomocysteinemia correlates with IR, increasing the oxidative stress. Oxidative stress causes endothelial dysfunction, hypertension and atherosclerosis. The objective of the study was to examine the correlation of homocysteine with siMS score and siMS risk score and with other MS co-founding factors. Methods: The study included 69 obese individuals (age over 30, body mass index [BMI] >25 kg/m2), classified into two groups: I-with MS (33 patients); II-without MS (36 patients). Measurements included: anthropometric parameters, lipids, glucose regulation parameters and inflammation parameters. IR was determined by homeostatic model assessment for insulin resistance (HOMA-IR). ATP III classification was applied for diagnosing MS. SiMS score was used as continuous measure of metabolic syndrome. Results: A significant difference between groups was found for C-reactive protein (CRP) (p<0.01) apolipoprotein (Apo) B, HOMA-IR and acidum uricum (p<0.05). siMS risk score showed a positive correlation with homocysteine (p=0.023), while siMS score correlated positively with fibrinogen (p=0.013), CRP and acidum uricum (p=0.000) and homocysteine (p=0.08). Homocysteine correlated positively with ApoB (p=0.036), HbA1c (p=0.047), HOMA-IR (p=0.008) and negatively with ApoE (p=0.042). Conclusions: Correlation of siMS score with homocysteine, fibrinogen, CRP and acidum uricum indicates that they are co-founding factors of MS. siMS risk score correlation with homocysteine indicates that hyperhomocysteinemia increases with age. Hyperhomocysteinemia is linked with genetic factors and family nutritional scheme, increasing the risk for atherosclerosis.

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Abstract 20140: Minibrain Relate Kinase / Dyrk1B Links Skeletal Muscle Glycolytic Metabolism with Insulin Resistance and Causes Metabolic Syndrome

Circulation ◽

10.1161/circ.130.suppl_2.20140 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Mohsen Fathzadeh ◽

Ali Reza Keramati ◽

Gwang Go ◽

Rajvir Singh ◽

Kazem Sarajzadeh ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Metabolic Syndrome ◽

Protein Expression ◽

Ppar Gamma ◽

Glycolytic Metabolism ◽

Expression Levels ◽

Fiber Composition ◽

Mutation Carriers ◽

Fast Twitch

We have identified a novel nonconservative mutation in Minibrain related serine/threonine kinase (Mirk/ Dyrk1B) in outlier kindreds with metabolic syndrome. The mutation substitutes cysteine for arginine (R102C) and segregates with most traits of metabolic syndrome, including central obesity, diabetes and hypertension. Oral glucose tolerance test (OGTT) in young nondiabetic mutation carriers revealed insulin resistance compared to noncarrier family members. Since skeletal muscle (SM) is the largest organ for glucose uptake and metabolism, we obtained Vastus Lateralis biopsies of mutation carriers and their unaffected relatives and examined them for gene/protein expression by deep RNA sequencing (RNA-Seq) and Western blot analysis and for fiber composition by immunostaining. The fiber composition data demonstrated fewer slow-twitch fibers (35% vs. 75%) and more fast -twitch fibers (65% vs. 25%) in SM of mutation carriers vs. controls. Interestingly, there were increased protein expression levels of fast-twitch fiber type proteins (MYH11, MYLPF), pyruvate dehydrogenase kinase, pyruvate kinase, and neuronal nitric oxide synthase in SM of mutation carriers vs. noncarriers. Consistent with these findings, the protein expression levels of the master regulator of cellular energy metabolism mitochondrial biogenesis, PPAR-gamma coactivator (PGC-1a), were reduced and the nuclear expression levels of FOXO1 and NFAT were increased. Similar findings were observed when wildtype and mutant (R102C) Dyrk1B were overexpressed in C2C12 cells. The overexpression of the kinase deficient Dyrk1B (Y271/273F) similarly resulted in reduced expression of PGC-1a and increased expression of nuclear FOXO1, suggesting kinase independent effects. Taken together, these findings suggest that enhanced kinase-independent activities of Dyrk1B, either through increased expression or by its gain of function mutation R102C induce insulin resistance by promoting glycolytic metabolism and reducing oxidative phosphorylation. In conclusion, Dyrk1B is a potential target for development of novel drugs that aim to enhance skeletal muscle insulin sensitivity.

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Encapsulated Mulberry Fruit Extract Alleviates Changes in an Animal Model of Menopause with Metabolic Syndrome

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/5360560 ◽

2019 ◽

Vol 2019 ◽

pp. 1-23 ◽

Cited By ~ 2

Author(s):

Jintanaporn Wattanathorn ◽

Supannika Kawvised ◽

Wipawee Thukham-mee

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Body Weight ◽

Weight Gain ◽

Protein Expression ◽

Body Weight Gain ◽

Atherogenic Index ◽

Fruit Extract ◽

Mulberry Fruit ◽

Oxidative Stress Status

Currently, the therapeutic strategy against metabolic syndrome and its complications is required due to the increasing prevalence and its impact. Due to the benefits of both mulberry fruit extract and encapsulation technology, we hypothesized that encapsulated mulberry fruit extract (MME) could improve metabolic parameters and its complication risk in postmenopausal metabolic syndrome. To test this hypothesis, female Wistar rats were induced experimental menopause with metabolic syndrome by bilateral ovariectomy (OVX) and high-carbohydrate high-fat (HCHF) diet. Then, they were orally given MME at doses of 10, 50, and 250 mg/kg BW for 8 weeks and the parameters, such as percentage of body weight gain, total cholesterol, triglycerides, HDL-C, LDL-C, atherogenic index, fasting blood glucose, plasma glucose area under the curve, serum angiotensin-converting enzyme (ACE), oxidative stress status, histology, and protein expression of PPAR-γ, TNF-α, and NF-κB in adipose tissues were determined. MME improved body weight gain, adiposity index, glucose intolerance, lipid profiles, atherogenic index, ACE, oxidative stress status, and protein expression of TNF-αand NF-κB. Moreover, MME attenuated adipocyte hypertrophy and enhanced PPAR-γexpression. Taken altogether, MME decreased metabolic syndrome and its complication via the increased PPAR-γexpression. Therefore, MME is the potential candidate for improving metabolic syndrome and its related complications. However, further research in clinical trial is still necessary.

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