Effects of exogenous ubiquitin in lethal endotoxemia

Majetschak, Matthias; Cohn, Stephen M.; Nelson, Jacob A.; Burton, Elizabeth H.; Obertacke, U.; Proctor, Kenneth G.

doi:10.1016/j.surg.2003.09.006

Cited by 51 publications

(76 citation statements)

References 29 publications

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“…In combination with previously described effects of ubiquitin in various shock models (19)(20)(21)45), these data indicate that selective CXCR4 activation stabilizes blood pressure during the cardiovascular stress response to hemorrhagic shock, providing an extended therapeutic window during which blood pressure can be restored with fluid resuscitation.…”

Section: Receptor Selectivitysupporting

confidence: 72%

“…As expected (19,21,(45)(46)(47) Next, we studied the effects of the CXCR4 and ACKR3 ligands that did not influence normal blood pressure in a hemorrhagic shock model. This model consisted of 30 min hemorrhage to a mean arterial blood pressure (MAP) of 30 mmHg followed by crystalloid fluid resuscitation to a MAP of 70 mmHg.…”

Section: Cxcr4 and Ackr3 Ligands Modulate Hemodynamics And Blood Presmentioning

confidence: 86%

“…Ubiquitin, a noncognate CXCR4 agonist (1,18), improved hemodynamic stability in large animal models of endotoxic and traumatic-hemorrhagic shock, while blockade of CXCR4 with the selective antagonist AMD3100 (1,1′-[1,4-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetra-decane octahydrochloride, generic name: plerixafor) impaired hemodynamic stability (19)(20)(21). Furthermore, AMD3100 decreased chronic hypoxia-induced pulmonary hypertension and the selective CXCR4 antagonist AMD3465 (N-[(4-[1,4,8,11-tetraazacyclotetradec-1-ylmethyl]phenyl)methyl]-2-pyridinemethanamine hexahydrobromide), which has a several-fold higher affinity for CXCR4 than AMD3100 (22), attenuated mineralocorticoid excess-induced hypertension in mice and rats (23,24).…”

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confidence: 99%

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Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3 Regulate Vascular α1-Adrenergic Receptor Function

Bach

Wong

Abhishek

et al. 2014

Mol Med

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Section: Receptor Selectivitysupporting

confidence: 72%

Section: Cxcr4 and Ackr3 Ligands Modulate Hemodynamics And Blood Presmentioning

confidence: 86%

mentioning

confidence: 99%

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Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3 Regulate Vascular α1-Adrenergic Receptor Function

Bach

Wong

Abhishek

et al. 2014

Mol Med

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“…Treatment with the CXCR4 antagonists AMD3100 and AMD3465 reduced blood pressure in experimental models of pulmonary arterial and systemic hypertension (6, 7). We have shown previously that AMD3100 reduces hemodynamic stability and blood pressure during the cardiovascular stress response to traumatic and hemorrhagic shock, whereas selective activation of CXCR4 with the noncognate agonist ubiquitin improves hemodynamic stability and increases systemic blood pressure after traumatic, hemorrhagic, and endotoxic shock (8)(9)(10)(11)(12)(13). Because in vivo pharmacological targeting of CXCR4 did not affect myocardial function, these findings suggested that effects of CXCR4 on hemodynamics and blood pressure are mediated via modulation of vascular function (9).…”

mentioning

confidence: 99%

Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function

Abhishek

Vana

Chavan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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116

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Recent evidence suggests that chemokine (C-X-C motif) receptor 4 (CXCR4) contributes to the regulation of blood pressure through interactions with α 1 -adrenergic receptors (ARs) in vascular smooth muscle. The underlying molecular mechanisms, however, are unknown. Using proximity ligation assays to visualize single-molecule interactions, we detected that α 1A/B -ARs associate with CXCR4 on the cell surface of rat and human vascular smooth muscle cells (VSMC). Furthermore, α 1A/B -AR could be coimmunoprecipitated with CXCR4 in a HeLa expression system and in human VSMC. A peptide derived from the second transmembrane helix of CXCR4 induced chemical shift changes in the NMR spectrum of CXCR4 in membranes, disturbed the association between α 1A/B -AR and CXCR4, and inhibited Ca 2+ mobilization, myosin light chain (MLC) 2 phosphorylation, and contraction of VSMC upon α 1 -AR activation. CXCR4 silencing reduced α 1A/B -AR:CXCR4 heteromeric complexes in VSMC and abolished phenylephrine-induced Ca 2+ fluxes and MLC2 phosphorylation. Treatment of rats with CXCR4 agonists (CXCL12, ubiquitin) reduced the EC 50 of the phenylephrineinduced blood pressure response three-to fourfold. These observations suggest that disruption of the quaternary structure of α 1A/B -AR:CXCR4 heteromeric complexes by targeting transmembrane helix 2 of CXCR4 and depletion of the heteromeric receptor complexes by CXCR4 knockdown inhibit α 1 -AR-mediated function in VSMC and that activation of CXCR4 enhances the potency of α 1 -AR agonists. Our findings extend the current understanding of the molecular mechanisms regulating α 1 -AR and provide an example of the importance of G protein-coupled receptor (GPCR) heteromerization for GPCR function. Compounds targeting the α 1A/B -AR:CXCR4 interaction could provide an alternative pharmacological approach to modulate blood pressure.CXCL12 | ubiquitin | AMD3100 | phenylephrine | blood pressure

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“…One study of swine infused with endotoxin found that exogenous ubiquitin infusion reduced mortality, respiratory failure, fl uid requirements, erythema, and edema over placebo. 76 Intriguingly, there is also evidence that extracellular ubiquitin may have antimicrobial properties as well. 77 As there is documented ubiquitin protease activity in several viruses, bacteria, and protozoa, 78 the potential for uncovering a pathogen-host ubiquitin and proteasome pathway interaction is promising.…”

Section: Biologic Roles and Potential Therapeutic Value Of The Extracmentioning

confidence: 99%

Ubiquitination and Proteolysis in Acute Lung Injury

Vadász

Weiss

Sznajder

2012

Chest

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CHEST The Ubiquitin Proteasome SystemThe Discovery of the Ubiquitin Proteasome System P rotein turnover plays an important role in a broad spectrum of cellular processes. Notably, approximately 3% to 5% of our cellular proteins are degraded and resynthesized daily. 1 Until the mid-1970s it was widely believed that all intracellular proteins were degraded at the same rate in lysosomes in a nonspecifi c manner, despite the fact that proteins have a wide range of half-lives. 1 The existence of a novel, highly regulated, and specifi c degradation pathway was fi rst proposed by Ciechanover and colleagues 2 and Hershko and colleagues, 3 which was in agreement with the discovery of an ATP-dependent proteolytic system in reticulocytes that lack lysosomes. 4 As it was described 2 years later, this novel degradation pathway was mediated by a small protein of 76 amino acid residues, termed ATP-dependent proteolysis factor-1 or ubiquitin. 5 , 6 The Ubiquitin Enzymatic Cascade During ubiquitination, target proteins become "marked" as ubiquitin covalently conjugates via its C-terminal glycine to protein substrates at the ´ -amino group of their lysine residues. 7 Conjugation of ubiquitin to a target protein occurs via an enzymatic cascade. 1 , 7 Ubiquitin is fi rst activated by an ATP-dependent E1 ubiquitin-activating enzyme by the formation of a thiolester bond between the E1 enzyme and ubiquitin. Ubiquitin is then transferred via a transthiolation Ubiquitination is a posttranslational modifi cation that regulates a variety of cellular functions depending on timing, subcellular localization, and type of tagging, as well as modulators of ubiquitin binding leading to proteasomal or lysosomal degradation or nonproteolytic modifi cations. Ubiquitination plays an important role in the pathogenesis of acute lung injury (ALI) and other lung diseases with pathologies secondary to infl ammation, mechanical ventilation, and decreased physical mobility. Particularly, ubiquitination has been shown to affect alveolar epithelial barrier function and alveolar edema clearance by targeting the Na,K-ATPase and epithelial Na 1 channels upon lung injury. Notably, the proteasomal system also exhibits distinct functions in the extracellular space, which may contribute to the pathogenesis of ALI and other pulmonary diseases. Better understanding of these mechanisms may ultimately lead to novel therapeutic modalities by targeting elements of the ubiquitination pathway.CHEST 2012; 141( 3 ): 763 -771Abbreviations : ALI 5 acute lung injury ; ARDS 5 acute respiratory distress syndrome ; ELF 5 epithelial lining fl uid ; ENaC 5 epithelial Na 1 channels ; NEDD8 5 neural precursor cell expressed, developmentally downregulated 8 ; pVHL 5 von Hippel Lindau protein; RING 5 really interesting new gene

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Effects of exogenous ubiquitin in lethal endotoxemia

Cited by 51 publications

References 29 publications

Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3 Regulate Vascular α1-Adrenergic Receptor Function

Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3 Regulate Vascular α1-Adrenergic Receptor Function

Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function

Ubiquitination and Proteolysis in Acute Lung Injury

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Effects of exogenous ubiquitin in lethal endotoxemia

Cited by 51 publications

References 29 publications

Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3 Regulate Vascular α1-Adrenergic Receptor Function

Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3 Regulate Vascular α1-Adrenergic Receptor Function

Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

Ubiquitination and Proteolysis in Acute Lung Injury

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Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function