Abrogated Leptin-Induced Cardiac Contractile Response in Ventricular Myocytes Under Spontaneous Hypertension

Wold, Loren E.; Relling, David P.; Duan, Jiaqi; Norby, Faye L.; Ren, Jun

doi:10.1161/hy0102.100777

Cited by 95 publications

(111 citation statements)

References 34 publications

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“…Neither inhibitor alone had any effect on PS. 5 Interestingly, both inhibitors not only Leptin resistance and insulin resistance KK Hintz et al abolished the leptin-induced decrease in PS but also unmasked a positive PS response in myocytes from both groups, suggesting that leptin may exert its inhibition on PS through JAK2 and/or MAP kinase pathways and also possess an intrinsic positive action on cardiac contraction ( Figure 6). …”

Section: Effect Of Leptin On Ps In the Presence Of Ag-490 And Sb203580mentioning

confidence: 95%

“…The duration and maximal velocity of shortening and relengthening (TPS, TR 90 and 7dL/dt) were not affected by leptin in either group (data not shown), consistent with our earlier findings. 5 To determine if leptin-induced inhibition of myocyte shortening was due to reduced availability of intracellular free Ca 2+ ([Ca 2+ ] i ), [Ca 2+ ] i in response to electrical stimuli in the presence of leptin (1-1000 nM) was examined. Figure 4d depicts that leptin elicited a concentration-dependent inhibition of DFFI, with maximal inhibitions of 19.6 and 14.3% in starch and sucrose myocytes, respectively.…”

Section: Experimental Animals and Plasma Leptin Levelmentioning

confidence: 99%

“…15,16,5 To examine if JAK/STAT and MAP kinase were involved in the leptin-induced cardiac contractile response under the current experimental setting, the effect of leptin on PS was re-examined by preincubating the cells with the JAK2 inhibitor AG-490 (20 mM) or the MAP kinase inhibitor SB203580 (20 mM) for 15 min. Neither inhibitor alone had any effect on PS.…”

Section: Effect Of Leptin On Ps In the Presence Of Ag-490 And Sb203580mentioning

confidence: 99%

“…1,3,4 Several signaling pathways have been confirmed in the cardiovascular regulation of leptin including Janus activated kinase (JAK), signal transducer and activators of transcription (STAT), mitogen activated protein (MAP) kinase and nitric oxide (NO). 4,5 However, little attempt has been made toward understanding the pathophysiological role of leptin in the onset of ventricular dysfunction under certain hyperleptinemic conditions such as obesity and hypertension.…”

Section: Introductionmentioning

confidence: 99%

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Insulin resistance induces hyperleptinemia, cardiac contractile dysfunction but not cardiac leptin resistance in ventricular myocytes

2003

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Insulin resistance is a metabolic syndrome commonly seen in obesity. Leptin, the obese gene product, plays a role in the regulation of cardiac function. Elevated leptin levels have been demonstrated under insulin-resistant states such as obesity and hypertension, although their role in cardiac dysfunction is unknown. This study was designed to determine the impact of prediabetic insulin resistance on leptin levels and leptin-induced cardiac contractile response. Whole-body insulin resistance was generated with a 10-week dietary sucrose feeding. Contractile and intracellular Ca 2+ properties were evaluated in ventricular myocytes using an IonOptixt system. The contractile indices analyzed included peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR 90 ), maximal velocity of shortening/relengthening (7dL/dt), fura-fluorescence intensity change (DFFI) and decay rate (t). Sucrose-fed rats displayed significantly elevated body weight and plasma leptin levels, depressed PS, 7dL/dt, shortened TPS, prolonged TR 90 and t, as well as reduced DFFI compared to the starch-fed control group. Leptin (1-1000 nM) elicited a concentration-dependent depression of PS and DFFI in myocytes from both starch and sucrose groups. Leptin-induced contractile depression was abolished by the nitric oxide synthase inhibitor No-nitro-L-arginine methyle ester, elevation of the extracellular Ca 2+ concentration, the Janus activated kinase 2 inhibitor AG-490 or the mitogen activated protein kinase inhibitor SB203580 in myocytes from both sucrose and starch groups. Moreover, AG-490 and SB203580 unmasked a positive response of PS in myocytes from both groups. These data indicate that insulin resistance directly induces hyperleptinemia and cardiac contractile dysfunction, without affecting leptin-mediated cardiac contractile function at the myocyte level.

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Section: Effect Of Leptin On Ps In the Presence Of Ag-490 And Sb203580mentioning

confidence: 95%

Section: Experimental Animals and Plasma Leptin Levelmentioning

confidence: 99%

Section: Effect Of Leptin On Ps In the Presence Of Ag-490 And Sb203580mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Insulin resistance induces hyperleptinemia, cardiac contractile dysfunction but not cardiac leptin resistance in ventricular myocytes

2003

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“…Cardiovascular regulation of the obese gene product leptin has attracted much attention because its deficiency or resistance leads to obesity and cardiovascular problems [3][4][5][6]. Leptin receptors exist in cardiomyocytes and are coupled to the signalling pathways regulating myocardial contractility [6,7] and cellular growth [5,8]. Mice lacking leptin (Lep/ Lep, formerly known as ob/ob) or its receptor (Lepr/Lepr, formerly known as db/db) develop cardiac hypertrophy and contractile dysfunction, consolidating a role for leptin in the maintenance of cardiac architecture and function [5,9,10].…”

Section: Introductionmentioning

confidence: 99%

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

et al. 2006

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Aims/hypothesis: Obesity is an independent risk factor for heart diseases but the underlying mechanism is not clear. This study examined cardiac contraction, oxidative stress, oxidative modification of sarco(endo) plasmic reticulum Ca 2+ -ATPase (SERCA) and the myosin heavy chain (MHC) isoform switch in obese mice. Methods: Mechanical properties were evaluated in ventricular myocytes from C57BL/6J lean and Lep/Lep obese mice (formerly known as ob/ob mice), including peak shortening (PS), time to 50 or 90% PS, time to 50 or 90% relengthening (TR 50 , TR 90 ), maximal velocity of shortening/relengthening (±dL/dt), intracellular Ca 2+ and its decay (τ). Oxidative stress, lipid peroxidation, protein damage and SERCA activity were assessed by glutathione/glutathione disulfide, malondialdehyde, protein carbonyl and 45 Ca 2+ uptake, respectively. NADPH oxidase was determined by immunoblotting. Results: Myocytes from Lep/Lep mice displayed depressed PS and ± dL/dt, prolonged TR 50 , TR 90 , elevated resting [Ca 2+ ] i , prolonged τ, reduced contractile capacity at high stimulus frequencies and diminished responsiveness to extracellular Ca 2+ compared with lean controls. Cardiac glutathione/glutathione disulfide was decreased whereas malondialdehyde, protein carbonyl, membrane p47 phox and membrane gp91 phox were increased in the Lep/Lep group. SERCA isoenzyme 2a was markedly modified by oxidation in Lep/ Lep hearts and associated with decreased 45 Ca 2+ uptake. The MHC isozyme displayed a shift from the α to the β isoform in Lep/Lep hearts. Short-term incubation of angiotensin II with myocytes mimicked the mechanical defects, SERCA oxidation and 45 Ca 2+ uptake seen in Lep/ Lep myocytes. Incubation of the NADPH oxidase inhibitor apocynin with Lep/Lep myocytes alleviated contractile defects without reversing SERCA oxidation or activity. Conclusions/interpretation: These data indicate that obesity-related cardiac defects may be related to NADPH oxidase activation, oxidative damage to SERCA and the MHC isozyme switch.

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Signal Transduction in the Cardiovascular System in Health and Disease

Srivastava¹,

Anand‐Srivastava²

2008

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except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Cover illustration:Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com PrefaceIn recent years, there has been a surge of interest in studies related to the role of a variety of signaling pathways in the control of cardiovascular physiology. Evidence has also accumulated to suggest that an aberration in the signal transduction pathways contributes to the pathophysiology of cardiovascular disease. Several components of the signaling pathways have been identified as potential targets for the development of new therapies of cardiovascular disease. Therefore, this volume has been compiled to highlight the contributions of different signaling systems in modulating normal cardiovascular functions and how a perturbation in these signaling events leads to abnormal cell functions and cardiovascular disorders. This volume has been divided into five sections dealing with five key signaling pathways regulating different aspects of cardiovascular physiology. The first section describes the role of G-protein-coupled receptor (GPCR) signaling in cardiovascular functions. In this section, Anand-Srivastava has elegantly summarized studies showing that the expression levels of various G-proteins as well as responsiveness of adenylyl cyclase systems to various stimuli such as β-adrenergic receptor (βAR) agonist and vasoactive peptides are defective in various models of hypertension, congestive heart failure (CHF), cardiac hypertrophy, and other diseases. Dent et al. have highlighted studies showing how the alterations in different components of the βAR signaling system contribute to CHF and suggest that βAR blockade could be used as a strategy to treat CHF. Continuing on the same theme, Vacek et al. have reviewed the pathophysiological mechanisms involved in CHF and sudden cardiac death, with an emphasis on the role of homocysteine-induced cross talk between NMDA receptor and GPCRs, while Moolman et al. have elaborated on the contributions of adenosine, cAMP/PKA system as well as p 38mapk in eliciting a cardioprotective response during early preconditioning. This section also has two elegant articles on the role of angiotensin II in cardiovascular pathophysiology: Engberding and Grindling and Schaffer and Mozaffari have provided indepth accounts of various signaling pathways induced by angiotensin II and how the dysregulation of this pathway contributes to heightened growth, proliferation, hypertrophy, and cell survival death responses associated with various cardiovascular abnormalities. v vi PrefaceThe second section foc...

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Abrogated Leptin-Induced Cardiac Contractile Response in Ventricular Myocytes Under Spontaneous Hypertension

Cited by 95 publications

References 34 publications

Insulin resistance induces hyperleptinemia, cardiac contractile dysfunction but not cardiac leptin resistance in ventricular myocytes

Insulin resistance induces hyperleptinemia, cardiac contractile dysfunction but not cardiac leptin resistance in ventricular myocytes

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

Signal Transduction in the Cardiovascular System in Health and Disease

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