Adrenomedullin binding protein-1 is downregulated during polymicrobial sepsis in the rat

Cui, Yingjie; Ji, Youxin; Wu, Rongqian; Zhou, Mian; Wang, Ping

doi:10.3892/ijmm.17.5.925

Cited by 6 publications

(9 citation statements)

References 23 publications

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“…The hepatic production and plasma concentration of AMBP-1 is dramatically reduced by over 50% during the late phase of cecal ligation and puncture (CLP)-induced sepsis in rats (12) and represents the pathophysiologic mechanism by which AM loses the ability to maintain its vasoactive function (9,10). The administration of AM and AMBP-1 in combination protects against cardiovascular instability and mortality in experimental sepsis by preventing the increase in peripheral vascular resistance and maintaining oxygen delivery to terminal organs.…”

Section: Adrenomedullin (Am)mentioning

confidence: 99%

Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ

Miksa

Cui

et al. 2007

The Journal of Immunology

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Sepsis is a critical inflammatory condition from which numerous patients die due to multiple organ failure and septic shock. The vasoactive hormone adrenomedullin (AM) and its binding protein (AMBP-1) are beneficial in sepsis by abrogating the progression to irreversible shock and decreasing proinflammatory cytokine release. To investigate the anti-inflammatory mechanism, we studied to determine the effect of the AM/AMBP-1 complex on peroxisome proliferator-activated receptor-γ (PPAR-γ) expression and activation by using RAW264.7 cells and a rat endotoxemia model. LPS treatment significantly decreased PPAR-γ expression in vivo and in vitro and was associated with increased TNF-α production. Treatment with AM/AMBP-1 for 4 h completely restored PPAR-γ levels in both models, resulting in TNF-α suppression. In a knockdown model using small interfering RNA in RAW264.7 macrophages, AM/AMBP-1 failed to suppress TNF-α production in the absence of PPAR-γ. LPS caused the suppression of intracellular cyclic AMP (cAMP), which was prevented by simultaneous AM/AMBP-1 treatment. Although incubation with dibutyryl cAMP significantly decreased LPS-induced ΤΝF-α release, it did not alter PPAR-γ expression. Through inhibition studies using genistein and PD98059 we found that the Pyk-2 tyrosine kinase-ERK1/2 pathway is in part responsible for the AM/AMBP-1-mediated induction of PPAR-γ and the anti-inflammatory effect. We conclude that AM/AMBP-1 is protective in sepsis due to its vasoactive properties and direct anti-inflammatory effects mediated through both the cAMP-dependent pathway and Pyk-2-ERK1/2-dependent induction of PPAR-γ.

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Section: Adrenomedullin (Am)mentioning

confidence: 99%

Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ

Miksa

Cui

et al. 2007

The Journal of Immunology

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“…In light of this report, it is plausible that AMBP-1 exerts its effects on AM by preventing the cleavage of AM by metalloproteinases. Recently we have shown that in a rat model of sepsis or endotoxemia, AMBP-1 gene and protein expression of hepatic tissue was significantly downregulated in the late phase of sepsis [19]. Even though AM is upregulated during sepsis primarily due to elevated levels of LPS [26], the vascular response to AM is significantly reduced in late sepsis [12].…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that the administration of LPS to normal Sprague-Dawley rats downregulates AMBP-1 production in the liver [19]. Since hepatocytes are the primary source of AMBP-1 biosynthesis in the liver, a co-culture strategy using hepatocyte and Kupffer cells were employed to determine whether LPS directly or by increasing pro-inflammatory cytokines from Kupffer cells downregulates AMBP-1 production.…”

Section: Lps Treatment In Co-culture Of Hepatocytes and Kupffer Cellsmentioning

confidence: 99%

“…The liver is a major source of AMBP-1 [17,18] and our previous studies indicated that both gene and protein expression of AMBP-1 are markedly reduced in hepatic tissues during the late phase of sepsis and endotoxemia [19]. However, it is unclear whether LPS directly or by increasing pro-inflammatory cytokines downregulates AMBP-1 in sepsis.…”

Section: Introductionmentioning

confidence: 99%

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Pro-inflammatory cytokines from Kupffer cells downregulate hepatocyte expression of adrenomedullin binding protein-1

Jacob

Zhou

et al. 2007

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late hypodynamic phase. Adrenomedullin (AM), a vasodilatory peptide, inhibits this transition from the early phase to the late phase. Adrenomedullin binding protein-1 (AMBP-1) enhances AM-mediated activities. The decrease of AMBP-1 levels in late sepsis reduces the vascular response to AM and produces the hypodynamic phase. Studies have indicated that the administration of LPS downregulates AMBP-1 production in the liver. Since hepatocytes are the primary source of AMBP-1 biosynthesis in the liver, we employed a co-culture strategy using hepatocyte and Kupffer cells to determine whether LPS directly or by increasing pro-inflammatory cytokines from Kupffer cells downregulates AMBP-1 production. Hepatocytes and Kupffer cells isolated from rats were co-cultured and treated with LPS for 24 h. LPS significantly attenuated AMBP-1 protein expression in a dose-dependent manner. Since AMBP-1 is basically a secretory protein, cell supernatants from co-culture cells treated with LPS were examined for AMBP-1 protein levels. LPS treatment caused a dose related decrease in AMBP-1 protein secretion. Similarly, LPS treatment produced a significant decrease in AMBP-1 protein expression in hepatocytes and Kupffer cells cultured using transwell inserts. LPS had no direct effect on AMBP-1 levels in cultured hepatocytes or Kupffer cells alone. To confirm that the observed effects in co-culture were due to the cytokines released from Kupffer cells, hepatocytes were treated with IL-1beta or TNF-alpha for 24 h and AMBP-1 expression was examined. The results indicated that both cytokines significantly inhibited AMBP-1 protein levels. Thus, pro-inflammatory cytokines released from Kupffer cells are responsible for downregulation of AMBP-1.

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“…Moreover, in vitro addition of AMBP-1 can completely restore AM hyporesponsiveness in the isolated blood vessels in a dose-response fashion (28). Although plasma levels of AM increase in sepsis (37), the levels of AMBP-1 decreased significantly in the blood and tissues under such conditions (28,52). The AM hyporesponsiveness observed in sepsis may be caused by the reduced AMBP-1 production.…”

Section: Discussionmentioning

confidence: 99%

Adrenomedullin and Adrenomedullin Binding Protein-1 Protect Endothelium-Dependent Vascular Relaxation in Sepsis

Zhou

Maitra

Wang

2007

Mol Med

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Downregulation of vascular endothelial constitutive nitric oxide synthase (ecNOS) contributes to the vascular hyporesponsiveness in sepsis. Although coadministration of the potent vasodilatory peptide adrenomedulin (AM) and the newly discovered AM binding protein (AMBP-1) maintains cardiovascular stability and reduces mortality in sepsis, it remains unknown whether AM/AMBP-1 prevents endothelial cell dysfunction. To investigate this possibility, we subjected adult male rats to sepsis by cecal ligation and puncture (CLP), with or without subsequent intravenous administration of the combination of AM (12 µg/kg) and AMBP-1 (40 µg/kg). Thoracic aortae were harvested 20 h after CLP (i.e., the late stage of sepsis) and endothelium-dependent vascular relaxation was determined by the addition of acetylcholine (ACh) in an organ bath system. In addition, ecNOS gene and protein expression was assessed by RT-PCR and immunohistochemistry, respectively. The results indicate that ACh-induced (i.e., endothelium-dependent) vascular relaxation was significantly reduced 20 h after CLP. Administration of AM/AMBP-1 prevented the reduction of vascular relaxation. In addition, ecNOS gene expression in aortic and pulmonary tissues was downregulated 20 h after CLP and AM/AMBP-1 attenuated such a reduction. Moreover, the decreased ecNOS staining in thoracic aortae of septic animals was prevented by the treatment with AM/AMBP-1. These results, taken together, indicate that AM/AMBP-1 preserves ecNOS and prevents reduced endothelium-dependent vascular relaxation (i.e., endothelial cell dysfunction) in sepsis. In light of our recent finding that AM/AMBP-1 improves organ function and reduces mortality in sepsis, it is most likely that the protective effect of these compounds on ecNOS is a mechanism responsible for the salutary effect of AM/AMBP-1 in sepsis.

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Adrenomedullin binding protein-1 is downregulated during polymicrobial sepsis in the rat

Cited by 6 publications

References 23 publications

Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ

Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ

Pro-inflammatory cytokines from Kupffer cells downregulate hepatocyte expression of adrenomedullin binding protein-1

Adrenomedullin and Adrenomedullin Binding Protein-1 Protect Endothelium-Dependent Vascular Relaxation in Sepsis

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