Myeloperoxidase upregulates endothelin receptor type B expression

Lau, Denise; Szöcs, Katalin; Klinke, Anna; Rudolph, Tanja K.; Rudolph, Volker; Streichert, Thomas; Blankenberg, Stefan; Baldus, Stephan

doi:10.1016/j.yjmcc.2013.12.007

Cited by 7 publications

(2 citation statements)

References 43 publications

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“…Interestingly, it has been recently observed that MPO led to upregulation of the endothelin receptor type B in endothelial cells, which was mediated by MPO-derived reactive species activating MAP-kinase pathways. 50 The MAP-kinase pathway might also mediate MPO-induced A 3 AR upregulation in diabetic WT mice, which can be investigated in further studies. Certainly, the fact that A 3 AR expression is also slightly but significantly increased in STZ-treated Mpo 2/2 mice indicates that receptor upregulation is not exclusively provoked by MPO.…”

Section: Discussionmentioning

confidence: 99%

Increased A3AR-dependent Vasoconstriction in Diabetic Mice Is Promoted by Myeloperoxidase

Nishat

Klinke

Baldus

et al. 2014

Journal of Cardiovascular Pharmacology

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Vascular dysfunction importantly contributes to mortality and morbidity in various cardiac and metabolic diseases. Among endogenous molecules regulating vascular tone is adenosine, with the adenosine A3 receptor (A3AR) exerting cardioprotective properties in ischemia and reperfusion. However, overexpression of A3AR is suggested to result in vascular dysfunction and inflammation. The leukocyte enzyme myeloperoxidase (MPO) is an important modulator of vascular function with nitric oxide-consuming and proinflammatory properties. Increased MPO plasma levels are observed in patients with cardiovascular disorders like heart failure, acute coronary syndromes, and arrhythmias. Given that vascular dysfunction and inflammation are also hallmarks of diabetes, the role of MPO in adenosine-dependent vasomotor function was investigated in a murine model of diabetes mellitus. Wild-type (WT) and MPO-deficient (Mpo) mice were treated with Streptozotocin (STZ), which induced an increase of MPO plasma levels in WT mice and led to enhanced aortic superoxide generation as assessed by dihydroethidium staining in STZ-treated WT mice as compared with controls. The vasoconstriction of aortic segments in response to the A3AR agonist Cl-IB-MECA (2-Chloro-N6-(3-iodobenzyl)-N-methyl-5-carbamoyladenosine) as determined by isometric force measurements was augmented in diabetic WT as compared with diabetic Mpo mice. Moreover, A3AR protein expression was enhanced in STZ-treated mice but was attenuated by MPO deficiency. The current data reveal an MPO-mediated increase of vascular A3AR expression under diabetic conditions, which leads to enhanced vasoconstriction in response to A3AR agonists and discloses an additional mechanism of MPO-mediated vascular dysfunction.

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Section: Discussionmentioning

confidence: 99%

Increased A3AR-dependent Vasoconstriction in Diabetic Mice Is Promoted by Myeloperoxidase

Nishat

Klinke

Baldus

et al. 2014

Journal of Cardiovascular Pharmacology

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“…The sources of ET-1 include vascular endothelial cells, macrophages, neutrophils, fibroblasts, and neurons (Barton and Yanagisawa 2008), and these cells also present endothelin receptors that are upregulated during inflammation, emphasizing the role of the endothelin system on maladaptive inflammatory responses and diseases (Pomonis et al 2001;Motte et al 2006;Lau et al 2014). Indeed, increased plasma levels of ET-1 occur in several pathological conditions associated with inflammation and pain, including Crohn's disease, ulcerative colitis, and rheumatoid arthritis (Miyasaka et al 1992;Letizia et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Bosentan, a mixed endothelin receptor antagonist, inhibits superoxide anion-induced pain and inflammation in mice

Serafim

Navarro

Zarpelon

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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Bosentan is a mixed endothelin receptor antagonist widely used to treat patients with pulmonary arterial hypertension, and the emerging literature suggests bosentan as a potent anti-inflammatory drug. Superoxide anion is produced in large amounts during inflammation, stimulates cytokine production, and thus contributes to inflammation and pain. However, it remains to be determined whether endothelin contributes to the inflammatory response triggered by the superoxide anion. The present study investigated the effects of bosentan in a mouse model of inflammation and pain induced by potassium superoxide, a superoxide anion donor. Male Swiss mice were treated with bosentan (10-100 mg/kg) by oral gavage, 1 h before potassium superoxide injection, and the inflammatory response was evaluated locally and at spinal cord (L4-L6) levels. Bosentan (100 mg/kg) inhibited superoxide anion-induced mechanical and thermal hyperalgesia, overt pain-like behavior (abdominal writhings, paw flinching, and licking), paw edema, myeloperoxidase activity (neutrophil marker) in the paw skin, and leukocyte recruitment in the peritoneal cavity. Bosentan also inhibited superoxide anion-induced interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) production, while it enhanced IL-10 production in the paw skin and spinal cord. Bosentan inhibited the reduction of antioxidant capacity (reduced glutathione, ferric reducing antioxidant power, and ABTS radical scavenging ability) induced by the superoxide anion. Finally, we demonstrated that intraplantar injection of potassium superoxide induces the mRNA expression of prepro-endothelin-1 in the paw skin and spinal cord. In conclusion, our results demonstrated that superoxide anion-induced inflammation, pain, cytokine production, and oxidative stress depend on endothelin; therefore, these responses are amenable to bosentan treatment.

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