Leptin signalling and leptin-mediated activation of human platelets: Importance of JAK2 and the phospholipases Cγ2 and A2

Dellas, Claudia; Schäfer, Katrin; Rohm, Ilonka; Lankeit, Mareike; Leifheit, Maren; Loskutoff, David J.; Hasenfuß, Gerd; Konstantinides, Stavros

doi:10.1160/th07-03-0213

Cited by 38 publications

(32 citation statements)

References 30 publications

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“…In this regard, leptin might promote the direct association of Src with activated JAK2 via N-terminal phosphotyrosines such as occur after angiotensin II stimulation 25. In addition, PLCγ, which becomes activated downstream of JAK2 in response to leptin,26 may facilitate the localization of Src within integrin signaling complexes 27. Consistently, our experiments revealed that Src kinase activation following leptin stimulation of CAC could be reduced by inhibition of PLCγ.…”

Section: Discussionsupporting

confidence: 78%

Leptin Enhances the Potency of Circulating Angiogenic Cells Via Src Kinase and Integrin αvβ5

Heida

Leifheit-Nestler

Schroeter

et al. 2010

ATVB

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Objective-To investigate the capacity of the adipokine leptin to promote angiogenesis by modulating the function of circulating angiogenic cells (CACs). Methods and Results-In vitro, leptin specifically promoted CAC adhesion to tubular endothelial structures and migration along outgrowing sprouts of endothelial cells. In vivo, stimulation of CACs with leptin increased their capacity to promote new vessel formation in the chorioallantoic membrane of chicken embryos and to improve neovascularization of ischemic murine hind limbs. These effects required the phosphorylation of ␣v␤5 integrins, which depended on the interaction of leptin with its receptor ObR, and on Janus kinase (JAK) 2-and phospholipase C (PLC) ␥-mediated activation of Src kinase. Protein tyrosine phosphatase 1B, a negative regulator of leptin signaling, was overexpressed in CACs from obese, hyperleptinemic individuals, and this was associated with insensitivity of CACs to the angiogenic effects of leptin. Weight loss (by [meanϮSD] 30Ϯ15 kg) normalized protein tyrosine phosphatase 1B expression in CACs and restored their responsiveness to leptin. A similar dose-dependent response was found after incubation of CACs from obese subjects with a protein tyrosine phosphatase 1B inhibitor ex vivo. Key Words: angiogenesis Ⅲ circulating angiogenic cells Ⅲ leptin Ⅲ obesity Ⅲ PTP1B Ⅲ Src kinase A ngiogenesis, the formation of new blood vessels from the existing vasculature, is a complex multistep process involving the proliferation, migration, and remodeling of endothelial cells in response to growth factors and cytokines. The adipose tissue-derived cytokine leptin has been shown to exert proangiogenic effects on endothelial cells 1,2 and leptinstimulated corneal neovascularization in rats and in leptindeficient ob/ob mice. 3 On the other hand, the prevention of leptin binding to its receptor inhibited angiogenesis, 4 and leptin receptor (ObR)-deficient mice exhibited reduced basal capillary density and defective revascularization of ischemic muscles. 5 Conclusion-Our See accompanying article on page 135Angiogenesis requires the interplay of various cell types, among which circulating angiogenic cells (CACs) appear to be of particular interest. These cells, formerly considered to represent a subpopulation of endothelial progenitor cells 6 and now regarded as a distinct (progenitor) cell type, 7 are derived from the peripheral blood after expansion in culture. They have been shown to augment neovascularization after tissue ischemia 8 and promote endothelial repair after vascular injury. 9 The vasculoprotective properties of CACs and other progenitor cells are defined by their ability to adhere to molecules released from injured tissues, allowing them to home and transmigrate at sites of injury or ischemia. 10 These steps are regulated by integrins, the transmembrane receptor heterodimers connecting the extracellular matrix to cytoskeletal and signaling molecules. More important, the activation status of integrins appears to be modulated by soluble growth fact...

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Section: Discussionsupporting

confidence: 78%

Leptin Enhances the Potency of Circulating Angiogenic Cells Via Src Kinase and Integrin αvβ5

Heida

Leifheit-Nestler

Schroeter

et al. 2010

ATVB

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“…This indicates that the LRb couples to Jak2 to activate PLC. Since leptin activates PLCγ2 in human platelets (Dellas et al, 2007), we perfused the selective PLCγ inhibitor ET-18-OCH3 (15 μM) and found that it potently blocked the effects of leptin (0.5 ± 0.5 pA, n = 7, p<0.001 versus control) (Figure 4D and E). Finally, to determine if the LRb is coupled through PLCγ1 or PLCγ2, we used scRTPCR to identify the expression of these transcripts in POMC neurons (Figure 4F).…”

Section: Resultsmentioning

confidence: 96%

Leptin Excites Proopiomelanocortin Neurons via Activation of TRPC Channels

Qiu¹,

Fang²,

Rønnekleiv³

et al. 2010

J. Neurosci.

180

254

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Leptin can exert its potent appetite-suppressing effects via activation of hypothalamic proopiomelanocortin (POMC) neurons. It depolarizes POMC neurons via activation of a yet unidentified nonselective cation current. Therefore, we sought to identify the conductance activated by leptin using whole-cell recording in EGFP-POMC neurons from transgenic mice. The TRPC channel blockers SKF96365 (1-[␤-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride), flufenamic acid, and 2-APB (2-aminoethyl diphenylborinate) potently inhibited the leptin-induced current. Also, lanthanum (La 3ϩ ) and intracellular Ca 2ϩ potentiated the effects of leptin. Moreover, the diacylglycerol-permeable analog OAG (2-acetyl-1-oleoyl-sn-glycerol) failed to activate any TRPC current. Using a Cs ϩ -gluconate-based internal solution, the leptin-activated current reversed near Ϫ20 mV. After replacement of external Na ϩ and K ϩ with Cs ϩ , the reversal shifted to near 0 mV, and the I/V curve exhibited a negative slope conductance at voltages more negative than Ϫ40 mV. Based on scRT-PCR, TRPC1 and TRPC4 -7 mRNA were expressed in POMC neurons, with TRPC5 being the most prevalent. The leptin-induced current was blocked by the Jak2 inhibitor AG490, the PI3 kinase inhibitor wortmannin, and the phospholipase C inhibitors, U73122 and ET-18-OCH3. Notably, we identified PLC␥1 transcripts in the majority of POMC neurons. Therefore, leptin through a Jak2-PI3 kinase-PLC␥ pathway activates TRPC channels, and TRPC1, 4, and 5 appear to be the key channels mediating the depolarizing effects of leptin in POMC neurons.

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“…Second, the other serine kinase(s), which is dependent on JAK2 but independent of p38 MAPK, may phosphorylate STAT1 or STAT3 in the leptin-stimulated keratinocytes; Akt or protein kinase C ␦ is involved in serine phosphorylation of STAT1 and STAT3 (37,38). It has been reported that JAK2 activated by leptin stimulates: 1) phosphatidylinositol 3-kinase, upstream of Akt and/or protein kinase C ␦, in Ob-Rb-transfected HEK293 cells (39); or 2) phospholipase C␥2 upstream of protein kinase C in platelets (40). Alternatively, STAT1 or STAT3 may have to be dimeric to be recognized by p38 MAPK or its downstream kinase, or STAT1 or STAT3 may have to translocate to the nucleus to move on to p38 MAPK or its downstream kinase; this is because p38 MAPK is known to be imported into the nuclei in leptin-stimulated rat cardiomyocytes (36).…”

Section: Discussionmentioning

confidence: 99%

Leptin Enhances Human β-Defensin-2 Production in Human Keratinocytes

Kanda

Watanabe

2008

Endocrinology

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Leptin, an adipocyte-derived cytokine/hormone, modulates innate and adaptive immunity. Human ␤-defensin-2 (hBD-2) produced by epidermal keratinocytes promotes cutaneous antimicrobial defense, inflammation, and wound repair. We examined the in vitro effects of leptin on hBD-2 production in human keratinocytes. hBD-2 secretion and mRNA expression were analyzed by ELISA and RT-PCR, respectively. Although leptin alone was ineffective, it enhanced IL-1␤-induced hBD-2 secretion and mRNA expression in keratinocytes. IL-1␤-and IL-1␤ plus leptin-induced hBD-2 production both were suppressed by antisense oligonucleotides against nuclear factor-B (NF-B) p50 and p65; the latter was also suppressed by antisense signal transducer and activator of transcription (STAT)1 and STAT3. IL-1␤ enhanced the transcriptional activity of NF-B, whereas leptin enhanced STAT1 and STAT3 activity. The p38 MAPK inhibitor SB202190 suppressed IL-1␤-and IL-1␤ plus leptin-induced hBD-2 production, IL-1␤-induced NF-B activity, and leptin-induced STAT1 and STAT3 activity; contrastingly, the Janus kinase (JAK) 2 inhibitor AG490 suppressed IL-1␤ plus leptin-induced hBD-2 production and leptin-induced STAT1 and STAT3 activity. IL-1␤ induced serine phosphorylation of inhibitory B␣, STAT1, and STAT3. Leptin induced tyrosine and serine phosphorylation of STAT1 and STAT3, both of which were suppressed by AG490, and serine phosphorylation was also suppressed by SB202190. IL-1␤ or leptin individually induced threonine/tyrosine phosphorylation of p38 MAPK, whereas only leptin induced tyrosine phosphorylation of JAK2, suggesting that leptin may enhance hBD-2 production in keratinocytes by activating STAT1 and STAT3 via JAK2 and p38 MAPK in cooperation with NF-B, which is activated by IL-1␤. Leptin may promote cutaneous antimicrobial defense, inflammation, and wound repair via hBD-2. (Endocrinology 149: 5189 -5198, 2008)

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Leptin signalling and leptin-mediated activation of human platelets: Importance of JAK2 and the phospholipases Cγ2 and A2

Cited by 38 publications

References 30 publications

Leptin Enhances the Potency of Circulating Angiogenic Cells Via Src Kinase and Integrin αvβ5

Leptin Enhances the Potency of Circulating Angiogenic Cells Via Src Kinase and Integrin αvβ5

Leptin Excites Proopiomelanocortin Neurons via Activation of TRPC Channels

Leptin Enhances Human β-Defensin-2 Production in Human Keratinocytes

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