Novel Synthetic, Host-defense Peptide Protects Against Organ Injury/Dysfunction in a Rat Model of Severe Hemorrhagic Shock

Yamada, Noriaki; Märtin, Lukas; Zechendorf, Elisabeth; Purvis, Gareth S. D.; Chiazza, Fausto; Varrone, Barbara.; Collino, Massimo; Shepherd, Joanna; Heinbockel, Lena; Gutsmann, Thomas; Correa, Wilmar; Brandenburg, Klaus; Marx, Gernot; Schuerholz, Tobias; Brohi, Karim; Thiemermann, Christoph

doi:10.1097/sla.0000000000002186

Cited by 17 publications

(37 citation statements)

References 37 publications

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“…Protein isolation and Western blot analysis. Semiquantitative Western blot analysis of caspase-3, caspase-9, Bax, and Bcl-2 was performed in murine heart tissue as previously before (48,49). For protein isolation, the tissue was homogenized in homogenization buffer (20 mM HEPES, pH 7.9, 1 mM MgCl 2 , 0.5 mM EDTA, 1% Nonidet P-40, 1 mM EGTA, 1 mM DTT, 0.5 mM PMSF, 1 μL/mL PIC) and centrifuged by 18,800 g for 40 minutes at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial sepsis

Zechendorf¹,

O'Riordan²,

Stiehler³

et al. 2020

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Section: Methodsmentioning

confidence: 99%

Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial sepsis

Zechendorf¹,

O'Riordan²,

Stiehler³

et al. 2020

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“…ELISA for ANXA1 Concentrations of ANXA1 in human plasma, mouse serum or protein lysates from heart and kidney were measured by ELISA as previously reported [21][22][23] /Tyr 204 on extracellular signal-regulated kinase (ERK1/2)/p-ERK1/2 (New England Biolabs) was measured by semi-quantitative western blot analyses in mouse heart and kidney tissue as described previously [20,25] (see ESM Methods for further details).…”

Section: Methodsmentioning

confidence: 99%

“…Activated Akt controls inflammatory and pro-survival responses [44]. Most notably, activation of the Akt survival pathway reduces organ injury in many conditions associated with inflammation including sepsis-induced organ dysfunction [20,45], haemorrhagic shock-induced organ dysfunction [25,46], myocardial infarction [47] and diabetes [48]. Specifically, in cardiac and renal ischaemia/reperfusion injury treatment with the Ac2-16 peptide tissue necrosis was reduced by activation of Akt [49,50].…”

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confidence: 99%

Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

et al. 2017

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Aims/hypothesis Microvascular complications in the heart and kidney are strongly associated with an overall rise in inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory molecule that limits and resolves inflammation. In this study, we have used a bedside to bench approach to investigate: (1) ANXA1 levels in individuals with type 1 diabetes; (2) the role of endogenous ANXA1 in nephropathy and cardiomyopathy in experimental type 1 diabetes; and (3) whether treatment with human recombinant ANXA1 attenuates nephropathy and cardiomyopathy in a murine model of type 1 diabetes. Methods ANXA1 was measured in plasma from individuals with type 1 diabetes with or without nephropathy and healthy donors. Experimental type 1 diabetes was induced in mice by injection of streptozotocin (STZ; 45 mg/kg i.v. per day for 5 consecutive days) in C57BL/6 or Anxa1 −/− mice. Diabetic mice were treated with human recombinant (hr)ANXA1(1 μg, 100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.) or vehicle (100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.).Results Plasma levels of ANXA1 were elevated in individuals with type 1 diabetes with/without nephropathy compared with healthy individuals (66.0 ± 4.2/64.0 ± 4 ng/ml vs 35.9 ± 2.3 ng/ml; p < 0.05). Compared with diabetic wild-type (WT) mice, diabetic Anxa1 −/− mice exhibited a worse diabetic phenotype and developed more severe cardiac (ejection fraction; 76.1 ± 1.6% vs 49.9 ± 0.9%) and renal dysfunction (proteinuria; 89.3 ± 5.0 μg/ mg vs 113.3 ± 5.5 μg/mg). Mechanistically, compared with nondiabetic WT mice, the degree of the phosphorylation of mitogenactivated protein kinases (MAPKs) p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) was significantly higher in non-diabetic Anxa1 −/− mice in both the heart and kidney, and was further enhanced after STZ-induced type 1 diabetes. Prophylactic treatment with hrANXA1 (weeks 1-13) attenuated both cardiac (ejection fraction; 54.0 ± 1.6% vs 72.4 ± 1.0%) and renal (proteinuria; 89.3 ± 5.0 μg/mg vs 53.1 ± 3.4 μg/mg) dysfunction associated with STZ-induced diabetes, while therapeutic administration of hrANXA1 (weeks 8-13), after significant cardiac and renal dysfunction had already developed, halted the further functional decline in cardiac and renal function seen in diabetic mice administered vehicle. In addition, administration of hrANXA1 attenuated the increase in phosphorylation of p38, JNK and ERK, and restored phosphorylation of Akt in diabetic mice. Conclusions/interpretationOverall, these results demonstrate that ANXA1 plasma levels are elevated in individuals with Christoph Thiemermann and Egle Solito contributed equally to this work.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-017-4469-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…Currently, there is no specific treatment for postoperative organ failure/dysfunction after TAAA repair, which is associated with high morbidity and mortality. We recently reported that a synthetic host-defense peptide that targets heparanase and heparan sulfate attenuates the organ injury/dysfunction associated with hemorrhagic shock (39, 40). Thus, we postulate that synthetic host-defense peptides may be promising therapeutics against postoperative organ failure/dysfunction after TAAA repair.…”

Section: Discussionmentioning

confidence: 99%

The β-d-Endoglucuronidase Heparanase Is a Danger Molecule That Drives Systemic Inflammation and Correlates with Clinical Course after Open and Endovascular Thoracoabdominal Aortic Aneurysm Repair: Lessons Learnt from Mice and Men

et al. 2017

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Thoracoabdominal aortic aneurysm (TAAA) is a highly lethal disorder requiring open or endovascular TAAA repair, both of which are rare, but extensive and complex surgical procedures associated with a significant systemic inflammatory response and high post-operative morbidity and mortality. Heparanase is a β-d-endoglucuronidase that remodels the endothelial glycocalyx by degrading heparan sulfate in many diseases/conditions associated with systemic inflammation including sepsis, trauma, and major surgery. We hypothesized that (a) perioperative serum levels of heparanase and heparan sulfate are associated with the clinical course after open or endovascular TAAA repair and (b) induce a systemic inflammatory response and renal injury/dysfunction in mice. Using a reverse-translational approach, we assessed (a) the serum levels of heparanase, heparan sulfate, and the heparan sulfate proteoglycan syndecan-1 preoperatively as well as 6 and 72 h after intensive care unit (ICU) admission in patients undergoing open or endovascular TAAA repair and (b) laboratory and clinical parameters and 90-day survival, and (c) the systemic inflammatory response and renal injury/dysfunction induced by heparanase and heparan sulfate in mice. When compared to preoperative values, the serum levels of heparanase, heparan sulfate, and syndecan-1 significantly transiently increased within 6 h of ICU admission and returned to normal within 72 h after ICU admission. The kinetics of any observed changes in heparanase, heparan sulfate, or syndecan-1 levels, however, did not differ between open and endovascular TAAA-repair. Postoperative heparanase levels positively correlated with noradrenalin dose at 12 h after ICU admission and showed a high predictive value of vasopressor requirements within the first 24 h. Postoperative heparan sulfate showed a strong positive correlation with interleukin-6 levels day 0, 1, and 2 post-ICU admission and a strong negative correlation with lactate clearance during the first 6 h post-ICU admission. Moreover, systemic administration of heparanase and heparan sulfate induced an inflammatory response and a small degree of renal dysfunction in mice. In conclusion, these results suggest that heparanase and heparan sulfate exhibit a substantial role as clinically relevant danger molecules and may serve as both, promising biomarkers and therapeutic targets in patients undergoing open or endovascular TAAA repair and, indeed, other conditions associated with significant systemic inflammation.

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Novel Synthetic, Host-defense Peptide Protects Against Organ Injury/Dysfunction in a Rat Model of Severe Hemorrhagic Shock

Abstract: Trauma-associated HS results in release of LL-37. The synthetic host-defense/antimicrobial peptide Pep19-4LF attenuates the organ injury/dysfunction associated with HS.

Cited by 17 publications

References 37 publications

Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial sepsis

Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial sepsis

Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

The β-d-Endoglucuronidase Heparanase Is a Danger Molecule That Drives Systemic Inflammation and Correlates with Clinical Course after Open and Endovascular Thoracoabdominal Aortic Aneurysm Repair: Lessons Learnt from Mice and Men

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