Medical Biochemistry Commons^™

Epoxyeicosatrienoic Acids Regulate Adipocyte Differentiation Of Mouse 3t3 Cells, Via Pgc-1Α Activation, Which Is Required For Ho-1 Expression And Increased Mitochondrial Function, Maayan Waldman, Lars Bellner, Luca Vanella, Joseph Schragenheim, Komal Sodhi, Shailendra P. Singh, Daohong Lin, Anand Lakhkar, Jiangwei Li, Edith Hochhauser, Michael Arad, Zbigniew Darzynkiewicz, Attallah Kappas, Nader G. Abraham

Nader G. Abraham

Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered preadipocyte function, enhanced peroxisome proliferation-activated receptor γ coactivator α (PGC-1α) expression, and increased mitochondrial function in the 3T3-L1 preadipocyte subjected to adipogenesis. Cells treated with EET resulted in an increase, P < 0.05, in PGC-1α and a decrease in mitochondria-derived ROS (MitoSox), P < 0.05. The EET increase in heme oxygenase-1 (HO-1) levels is dependent on activation of PGC-1α as cells deficient in PGC-1α (PGC-1α knockout adipocyte cell) have an impaired ability to express HO-1, P …

Pnaktide Inhibits Na/K-Atpase Reactive Oxygen Species Amplification And Attenuates Adipogenesis, Komal Sodhi, Kyle Maxwell, Yanling Yan, Jiang Liu, Muhammad Chaudhry, Morgan Getty, Zijian Xie, Nader G. Abraham, Joseph I. Shapiro Md

Nader G. Abraham

Obesity has become a worldwide epidemic and is a major risk factor for metabolic syndrome. Oxidative stress is known to play a role in the generation and maintenance of an obesity phenotype in both isolated adipocytes and intact animals. Because we had identified that the Na/K-ATPase can amplify oxidant signaling, we speculated that a peptide designed to inhibit this pathway, pNaKtide, might ameliorate an obesity phenotype. To test this hypothesis, we first performed studies in isolated murine preadipocytes (3T3L1 cells) and found that pNaKtide attenuated oxidant stress and lipid accumulation in a dose-dependent manner. Complementary experiments in C57Bl6 mice fed …

Antioxidants Condition Pleiotropic Vascular Responses To Exogenous H2o2: Role Of Modulation Of Vascular Tp Receptors And The Heme Oxygenase System, Nitin Puri, Fan Zhang, Sumit R. Monu, Komal R. Sodhi, Lars Bellner, Brian D. Lamon, Yilun Zhang, Nader G. Abraham, Alberto Nasjletti

Nader G. Abraham

Aims: Hydrogen peroxide (H(2)O(2)), a nonradical oxidant, is employed to ascertain the role of redox mechanisms in regulation of vascular tone. Where both dilation and constriction have been reported, we examined the hypothesis that the ability of H(2)O(2) to effect vasoconstriction or dilation is conditioned by redox mechanisms and may be modulated by antioxidants. Results: Exogenous H(2)O(2) (0.1-10.0 μM), dose-dependently reduced the internal diameter of rat renal interlobular and 3rd-order mesenteric arteries (p<0.05). This response was obliterated in arteries pretreated with antioxidants, including tempol, pegylated superoxide dismutase (PEG-SOD), butylated hydroxytoluene (BHT), and biliverdin (BV). However, as opposed to tempol …

Apolipoprotein A-I Mimetic Peptide L-4f Prevents Myocardial And Coronary Dysfunction In Diabetic Mice, C. Vecoli, J. Cao, D. Neglia, K. Inoue, Komal Sodhi, L. Vanella, K. K. Gabrielson, D. Bedja, N. Paolocci, A. L'Abbate, Nader G. Abraham

Nader G. Abraham

Diabetes is a major health problem associated with adverse cardiovascular outcomes. The apolipoprotein A-I mimetic peptide L-4F is a putative anti-diabetic drug, has antioxidant and anti-inflammatory proprieties and improves endothelial function. In obese mice L-4F increases adiponectin levels, improving insulin sensitivity and reducing visceral adiposity. We hypothesized that the pleiotropic actions of L-4F can prevent heart and coronary dysfunction in a mouse model of genetically induced Type II diabetes. We treated db/db mice with either L-4F or vehicle for 8 weeks. Trans-thoracic echocardiography was performed; thereafter, isolated hearts were subjected to ischemia/reperfusion (IR). Glucose, insulin, adiponectin, and pro-inflammatory cytokines (IL-1β, …

Dysglycemia Induces Abnormal Circadian Blood Pressure Variability, Sivarajan Kumarasamy, Kathirvel Gopalakrishnan, Dong Hyun Kim, Nader G. Abraham, William D. Johnson, Bina Joe, Alok K. Gupta

Nader G. Abraham

Background: Prediabetes (PreDM) in asymptomatic adults is associated with abnormal circadian blood pressure variability (abnormal CBPV).

Hypothesis: Systemic inflammation and glycemia influence circadian blood pressure variability.

Methods: Dahl salt-sensitive (S) rats (n = 19) after weaning were fed either an American (AD) or a standard (SD) diet. The AD (high-glycemic-index, high-fat) simulated customary human diet, provided daily overabundant calories which over time lead to body weight gain. The SD (low-glycemic-index, low-fat) mirrored desirable balanced human diet for maintaining body weight. Body weight and serum concentrations for fasting glucose (FG), adipokines (leptin and adiponectin), and proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1) …

Ho-1 Induction Improves The Type-1 Cardiorenal Syndrome In Mice With Impaired Angiotensin Ii–Induced Lymphocyte Activation, Sumit R. Monu, Paola Pesce, Komal Sodhi, Massimo Boldrin, Nitin Puri, Larisa Fedorova, David Sacerdoti, Stephen J. Peterson, Nader G. Abraham, Attallah Kappas

Nader G. Abraham

Type-1 cardiorenal syndrome, characterized by acute kidney dysfunction secondary to cardiac failure and renal arteriolar vasoconstriction, is mediated by the renin–angiotensin–aldosterone axis and sympathetic nervous system activation. Previous reports indicate that angiotensin II modulates immune function and causes recruitment and activation of T-lymphocytes. The goal of this study was to evaluate the effects of postischemic heart failure on renal morphology and circulation and the beneficial effects of heme oxygenase-1 (HO-1) induction in T-lymphocyte–suppressed severe combined immune deficiency (SCID) mice. Mice were divided into 4 groups: sham, myocardial infarction (MI), MI treated with an HO-1 inducer, cobalt protoporphyrin, and with or …

Apo A1 Mimetic Rescues The Diabetic Phenotype Of Ho-2 Knockout Mice Via An Increase In Ho-1 Adiponectin And Lkbi Signaling Pathway, Jian Cao, Nitin Puri, Komal Sodhi, Lars Bellner, Nader G. Abraham, Attallah Kappas

Nader G. Abraham

Insulin resistance, with adipose tissue dysfunction, is one of the hallmarks of metabolic syndrome. We have reported a metabolic syndrome-like phenotype in heme oxygenase (HO)-2 knockout mice, which presented with concurrent HO-1 deficiency and were amenable to rescue by an EET analog. Apo A-I mimetic peptides, such as L-4F, have been shown to induce HO-1 expression and decrease oxidative stress and adiposity. In this study we aimed to characterize alleviatory effects of HO-1 induction (if any) on metabolic imbalance observed in HO-2 KO mice. In this regard, HO-2(−/−) mice were injected with 2 mg/kg/day L-4F, or vehicle, i.p., for 6 …

Cyclooxygenase-2 Dependent Metabolism Of 20-Hete Increases Adiposity And Adipocyte Enlargement In Mesenchymal Stem Cell-Derived Adipocytes, Dong Kim, Nitin Puri, Komal Sodhi, John Falck, Nader Abraham, Joseph Shapiro, Michal Schwartzman

Nader G. Abraham

Abstract 20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE), a product of the cytochrome P450 (CYP)-catalyzed [1] -hydroxylation of arachidonic acid, induces oxidative stress and, in clinical studies, is associated with increased body mass index (BMI) and the metabolic syndrome. This study was designed to examine the effects of exogenous 20- HETE on mesenchymal stem cell (MSC)-derived adipocytes. The expression levels of CYP4A11 and CYP4F2 (major 20-HETE synthases in humans) in MSCs decreased during adipocyte differentiation; however, exogenous administration of 20-HETE (0.1–1 M) increased adipogenesis in a dose dependent manner in these cells ( P < 0.05). The inability of a 20-HETE analog to reproduce these …

Pparδ Binding To Heme Oxygenase 1 Promoter Prevents Angiotensin Ii-Induced Adipocyte Dysfunction In Goldblatt Hypertensive Rats, Komal Sodhi, Nitin Puri, Dong Kim, Terry Hinds, Lance Stechschulte, Gaia Favero, Luigi Rodella, Joseph Shapiro, David Jude, Nader Abraham

Nader G. Abraham

Abstract:

OBJECTIVE: Renin–angiotensin system (RAS) regulates adipogenic response with adipocyte hypertrophy by increasing oxidative stress. Recent studies have shown the role of peroxisome proliferator-activated receptor-d (PPARδ) agonist in attenuation of angiotensin II-induced oxidative stress. The aim of this study was to explore a potential mechanistic link between PPARδ and the cytoprotective enzyme heme oxygenase-1 (HO-1) and to elucidate the contribution of HO-1 to the adipocyte regulatory effects of PPARδ agonism in an animal model of enhanced RAS, the Goldblatt 2 kidney 1 clip (2K1C) model.

METHOD: We first established a direct stimulatory effect of the PPARδ agonist (GW 501516) on …

Increased Heme-Oxygenase 1 Expression In Mesenchymal Stem Cell-Derived Adipocytes Decreases Differentiation And Lipid Accumulation Via Upregulation Of The Canonical Wnt Signaling Cascade, Luca Vanella, Komal Sodhi, Dong Kim, Nitin Puri, Mani Maheshwari, Terry Hinds, Lars Bellner, Dov Goldstein, Stephen Peterson, Joseph Shapiro, Nader Abraham

Nader G. Abraham

Introduction: Heme oxygenase (HO), a major cytoprotective enzyme, attenuates oxidative stress and obesity. The canonical Wnt signaling cascade plays a pivotal role in the regulation of adipogenesis. The present study examined the interplay between HO-1and the Wnt canonical pathway in the modulation of adipogenesis in mesenchymal stem cell (MSC)-derived adipocytes. Methods: To verify the role of HO-1 in generating small healthy adipocytes, cobalt protoporphyrin (CoPP), inducer of HO-1, was used during adipocyte differentiation. Lipid accumulation was measured by Oil red O staining and lipid droplet size was measured by BODIPY staining. Results: During adipogenesis in vitro, differentiating pre-adipocytes display transient …