Leptin Signaling in Human Peripheral Blood Mononuclear Cells, Activation of p38 and p42/44 Mitogen-Activated Protein (MAP) Kinase and p70 S6 Kinase

Brink, Gijs R. van den; O’Toole, Tom; Hardwick, James C.H.; Boogaardt, D. E. van den; Versteeg, Henri H.; Deventer, Sjoerd van; Peppelenbosch, Maikel P.

doi:10.1006/mcbr.2001.0270

Cited by 56 publications

(31 citation statements)

References 44 publications

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“…13,15 To determine whether JAK2 and MAP kinase were involved in the leptin-induced cardiac contractile response, the effect of leptin on PS was re-examined by preincubating the cells with the JAK2 inhibitor AG-490 (20 mol/L) or the MAP kinase inhibitor SB203580 (20 mol/L) for 15 minutes. Neither inhibitor alone had any effect on PS.…”

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

confidence: 99%

“…11,12 The signaling pathway underlying the cardiovascular regulation of leptin has not been well defined, although evidence has suggested that leptin may interact with its specific leptin receptors (Ob-Rs) 13 and act through the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) 13,14 or mitogen-activated protein (MAP) kinase pathways. 15 Leptin levels have been shown to be elevated in hypertension, suggesting a potential link between hyperleptinemia and cardiovascular dysfunction in hypertension. 16,17 However, current knowledge of the relationship between leptin and hypertension has been primarily limited to the vascular system.…”

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confidence: 99%

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

et al. 2002

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Abstract-Leptin regulates cardiovascular function. Leptin levels are elevated in obesity and hypertension and may play a role in cardiovascular dysfunctions in these comorbidities. This study was designed to determine the influence of hypertension on the cardiac contractile response of leptin. Mechanical and intracellular Ca 2ϩ properties were evaluated using an IonOptix system in ventricular myocytes from spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats. The contractile properties included peak shortening (PS), duration and maximal velocity of shortening/relengthening (TPS/TR 90 , ϮdL/dt), and fura-fluorescence intensity change (⌬FFI). NO and nitric oxide synthase (NOS) activity were assessed by the Griess and the 3 H-arginine/citrulline conversion assays, respectively. The leptin receptor (Ob-R) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were evaluated by Western blot analysis. SHR animals displayed significantly elevated blood pressure and plasma leptin levels. Leptin elicited a concentration-dependent inhibition of PS and ⌬FFI in WKY, but not in SHR myocytes. Leptin did not affect TPS, TR 90 , or Ϯ dL/dt. The difference in leptin-induced contractile response between the WKY and the SHR groups was abolished by the NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), but not by elevated extracellular Ca 2ϩ . Either the JAK2 inhibitor AG-490 or the mitogen-activated protein (MAP) kinase inhibitor SB203580 abrogated the leptin-induced response in the WKY myocytes, whereas AG-490 unmasked a negative response in PS in the SHR myocytes. SHR myocytes displayed similar Ob-R protein abundance and basal NO levels, a blunted leptin-induced increase in NOS activity as well as enhanced basal STAT3 levels compared with the WKY group. These data indicate that the leptin-induced cardiac contractile response is abolished by spontaneous hypertension, possibly because of mechanisms involving altered JAK/STAT, MAP kinase signaling, and NO response. Key Words: signal transduction Ⅲ hypertension, obesity Ⅲ myocytes Ⅲ cardiac function Ⅲ kinase Ⅲ nitric oxide E pidemiological evidence revealed that over 60% of US adults are considered overweight. 1,2 Obesity is shown to predispose the development of various comorbidities such as hypertension, diabetes, and dyslipidemia. 2,3 Both clinical and experimental evidence has implicated hypertension as the most common comorbidity associated with obesity. 2 Although hypertension and obesity often exist concurrently, leading to ventricular dysfunction, obesity itself is known to enhance the development of other risk factors, such as hypertension and dyslipidemia. 4,5 Leptin, the obesity gene (ob) product, regulates energy metabolism and expenditure. Leptin enhances sympathetic nervous activity, 6 which may be directly associated with increased body fat composition. 7-9 Leptin infusion was shown to reduce blood pressure and heart rate, which may be reversed by nitric oxide synthase (NOS) inhibition. 10,11 Recent...

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

confidence: 99%

mentioning

confidence: 99%

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

et al. 2002

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“…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%

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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“…But leptin can also use other signaling cascades via JAK activation. Among these are p38 (31), extracellular signal-regulated kinase (ERK1/2) (2,(31)(32)(33)(34)(35)(36), and c-Jun terminal/stressactivated protein kinases (37) of the mitogen-activated protein kinase (MAPK) family members. Furthermore, leptin was found to generate increased amounts of H 2 O 2 in isolated vascular endothelial cells in association with atherogenic processes (37,38).…”

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confidence: 99%

Leptin Stimulates Tissue Inhibitor of Metalloproteinase-1 in Human Hepatic Stellate Cells

Cao

Mak

Ren

et al. 2004

Journal of Biological Chemistry

154

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Leptin is recognized as a profibrogenic hormone in the liver, but the mechanisms involved have not been clarified. The tissue inhibitor of metalloproteinase (TIMP)-1, which acts through inhibition of collagen degradation, is synthesized by activated hepatic stellate cells (HSC) in response to fibrogenic substances. The capacity of leptin to induce TIMP-1 and its signaling molecules were investigated in a human HSC cell line, LX-2. Leptin stimulated TIMP-1 protein, mRNA, and promoter activity. JAK1 and -2, as well as STAT3 and -5, were activated. After leptin, there was increased expression of tyrosine 1141-phosphorylated leptin receptor, which may contribute to STAT3 activation. AG 490, a JAK inhibitor, blocked JAK phosphorylation with concomitant inhibition of STAT activation, TIMP-1 mRNA expression, and promoter activity. Leptin also induced an oxidative stress, which was inhibited by AG 490, indicating a JAK mediation process. ERK1/2 MAPK and p38 were activated, which was prevented by catalase, indicating an H 2 O 2 -dependent mechanism. Catalase treatment resulted in total suppression of TIMP-1 mRNA expression and promoter activity. SB203580, a p38 inhibitor, prevented p38 activation and reduced TIMP-1 message half-life with down-regulation of TIMP-1 mRNA. These changes were reproduced by overexpression of the dominant negative p38␣ and p38␤ mutants. PD098059, an ERK1/2 inhibitor, opposed ERK1/2 activation and TIMP-1 promoter activity, leading to TIMP-1 mRNA down-regulation. Thus, leptin has a direct action on liver fibrogenesis by stimulating TIMP-1 production in activated HSC. This process appears to be mediated by the JAK/STAT pathway via the leptin receptor long form and the H 2 O 2 -dependent p38 and ERK1/2 pathways via activated JAK.

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Leptin Signaling in Human Peripheral Blood Mononuclear Cells, Activation of p38 and p42/44 Mitogen-Activated Protein (MAP) Kinase and p70 S6 Kinase

Cited by 56 publications

References 44 publications

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

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

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

Leptin Stimulates Tissue Inhibitor of Metalloproteinase-1 in Human Hepatic Stellate Cells

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