Up-regulation of endothelin type B receptors in the human internal mammary artery in culture is dependent on protein kinase C and mitogen-activated kinase signaling pathways

Nilsson, David; Gustafsson, Lotta; Wackenfors, Angelica; Gesslein, Bodil; Edvinsson, Lars; Paulsson, Per; Ingemansson, Richard; Malmsjö, Malin

doi:10.1186/1471-2261-8-21

Cited by 8 publications

(3 citation statements)

References 42 publications

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“…Culture of human internal mammary arteries induces PKC-and MAPK-dependent upregulation of ET B receptors in the smooth muscle cells [42]. The results agree well with our previous studies demonstrating that organ culture of rat mesenteric and cerebral arteries induces upregulation of ET B receptors in the smooth muscle cells, and this upregulation occurs via activation of NF-κB [14] and ERK1/2 MAPK [29,43].…”

supporting

confidence: 82%

Minimally modified LDL upregulates endothelin type B receptors in rat coronary artery via ERK1/2 MAPK and NF-κB pathways

Cao

Yuan

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Minimally modified low density lipoprotein (mmLDL) is a well-known risk factor for coronary artery disease. Upregulation of vascular endothelin type B (ET B ) receptors on the vascular smooth muscle cells is predicted to be the molecular mechanism that leads to cardiovascular pathogenesis. The objective of the present study was to examine the hypothesis that mmLDL upregulates ET B receptors in rat coronary artery. The contractile responses to sarafotoxin 6c (ET B receptor agonist) were studied using a sensitive myograph. ETB receptor mRNA and protein expression was determined using real-time PCR and Western blot analysis.The results showed that organ culture increased the contractile responses induced by sarafotoxin 6c and the levels of ET B receptor mRNA and protein. This increase was further enhanced by the addition of mmLDL (10 μg/mL). Specific ERK1/2 inhibitors (SB386023 and U0126) and an NF-κB inhibitor (wedelolactone) attenuated the mmLDL-increased ET B receptor-mediated contraction and ET B receptor mRNA and protein levels. Wedelolactone significantly attenuated the mmLDL-decreased IκBα protein expression. Consistent with this result, IκBα protein expression was significantly decreased by culture withmmLDL compared to the level of expression in the organ culture group. However, the JNK inhibitor, SP600125 or p38 pathway inhibitor, SB203580 did not inhibit mmLDL-enhanced effects. The PKC inhibitor, staurosporine attenuated only culture-alone-increased effects. In conclusion, mmLDL upregulates the ETB receptors in rat coronary arterial smooth muscle cells, mainly via activation of the ERK1/2 MAPK and the downstream transcriptional factor NF-κB.

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supporting

confidence: 82%

Minimally modified LDL upregulates endothelin type B receptors in rat coronary artery via ERK1/2 MAPK and NF-κB pathways

Cao

Yuan

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…ET-1 activates NADPH oxidase and causes inflammation in hypertensive animals [33, 34] and, vice versa, NADPH oxidase-derived superoxide formation increases ET-1-mediated vasoconstriction [35], most likely mediated by oxidative stress-induced preproET-1 gene promoter activation [36, 37]. GTN therapy also activates protein kinase C (PKC) [19] and increased PKC activity induces the expression of the ET B receptor [75]. PKC is also required for the activation of the NADPH oxidase isoforms NOX-1 and NOX-2.…”

Section: Discussionmentioning

confidence: 99%

The Endothelin Receptor Antagonist Macitentan Improves Isosorbide‐5‐Mononitrate (ISMN) and Isosorbide Dinitrate (ISDN) Induced Endothelial Dysfunction, Oxidative Stress, and Vascular Inflammation

Steven

Oelze

Hausding

et al. 2018

Oxidative Medicine and Cellular Longevity

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Objective Organic nitrates such as isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) are used for the treatment of patients with chronic symptomatic stable coronary artery disease and chronic congestive heart failure. Limiting side effects of these nitrovasodilators include nitrate tolerance and/or endothelial dysfunction mediated by oxidative stress. Here, we tested the therapeutic effects of the dual endothelin (ET) receptor antagonist macitentan in ISMN- and ISDN-treated animals. Methods and Results Organic nitrates (ISMN, ISDN, and nitroglycerin (GTN)) augmented the oxidative burst and interleukin-6 release in cultured macrophages, whereas macitentan decreased the oxidative burst in isolated human leukocytes. Male C57BL/6j mice were treated with ISMN (75 mg/kg/d) or ISDN (25 mg/kg/d) via s.c. infusion for 7 days and some mice in addition with 30 mg/kg/d of macitentan (gavage, once daily). ISMN and ISDN in vivo therapy caused endothelial dysfunction but no nitrate (or cross-)tolerance to the organic nitrates, respectively. ISMN/ISDN increased blood nitrosative stress, vascular/cardiac oxidative stress via NOX-2 (fluorescence and chemiluminescence methods), ET1 expression, ET receptor signaling, and markers of inflammation (protein and mRNA level). ET receptor signaling blockade by macitentan normalized endothelial function, vascular/cardiac oxidative stress, and inflammatory phenotype in both nitrate therapy groups. Conclusion ISMN/ISDN treatment caused activation of the NOX-2/ET receptor signaling axis leading to increased vascular oxidative stress and inflammation as well as endothelial dysfunction. Our study demonstrates for the first time that blockade of ET receptor signaling by the dual endothelin receptor blocker macitentan improves adverse side effects of the organic nitrates ISMN and ISDN.

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“…Upon activation, PKCε undergoes translocation from the cytoplasm to the cell membrane (particulate fractions) to phosphorylate its targets, including extracellular signal-regulated kinases (ERK) (19)(20)(21). ERK1/2 are considered the downstream kinases of PKC and are implicated in a wide range of cellular processes, including cell growth, proliferation to apoptosis (22,23). The ERK pathway is involved in cardiac development and hypertrophy (24).…”

Section: Introductionmentioning

confidence: 99%

β-adrenergic stimulation activates protein kinase Cε and induces extracellular signal-regulated kinase phosphorylation and cardiomyocyte hypertrophy

Cai

Liu

et al. 2015

Molecular Medicine Reports

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The cardiac adrenergic signaling pathway is important in the induction of cardiac hypertrophy. The cardiac adrenergic pathway involves two main branches, phospholipase C (PLC)/protein kinase C (PKC) and the adenylate cyclase (cAMPase)/protein kinase A (PKA) signaling pathways. It is hypothesized that PLC/PKC and cAMPase/PKA are activated by the α‑adrenergic receptor (αAR) and the β‑adrenergic receptor (βAR), respectively. Previous studies have demonstrated that exchange protein directly activated by cAMP (Epac), a guanine exchange factor, activates phospholipase Cε. It is possible that there are βAR‑activated PKC pathways mediated by Epac and PLC. In the present study, the role of Epac and PLC in βAR activated PKC pathways in cardiomyocytes was investigated. It was found that PKCε activation and translocation were induced by the βAR agonist, isoproterenol (Iso). Epac agonist 8‑CPT‑2'OMe‑cAMP also enhanced PKCε activation. βAR stimulation activated PKCε in the cardiomyocytes and was regulated by Epac. Iso‑induced change in PKCε was not affected in the cardiomyocytes, which were infected with adenovirus coding rabbit muscle cAMP‑dependent protein kinase inhibitor. However, Iso‑induced PKCε activation was inhibited by the PLC inhibitor, U73122. The results suggested that Iso‑induced PKCε activation was independent of PKA, but was regulated by PLC. To further investigate the downstream signal target of PKCε activation, the expression of phosphorylated extracellular signal‑regulated kinase (pERK)1/2 and the levels of ERK phosphorylation was analyzed. The results revealed that Iso‑induced PKCε activation led to an increase in the expression of pERK1/2. ERK phosphorylation was inhibited by the PKCε inhibitor peptide. Taken together, these data demonstrated that the βAR is able to activate PKCε dependent on Epac and PLC, but independent of PKA.

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Up-regulation of endothelin type B receptors in the human internal mammary artery in culture is dependent on protein kinase C and mitogen-activated kinase signaling pathways

Cited by 8 publications

References 42 publications

Minimally modified LDL upregulates endothelin type B receptors in rat coronary artery via ERK1/2 MAPK and NF-κB pathways

Minimally modified LDL upregulates endothelin type B receptors in rat coronary artery via ERK1/2 MAPK and NF-κB pathways

The Endothelin Receptor Antagonist Macitentan Improves Isosorbide‐5‐Mononitrate (ISMN) and Isosorbide Dinitrate (ISDN) Induced Endothelial Dysfunction, Oxidative Stress, and Vascular Inflammation

β-adrenergic stimulation activates protein kinase Cε and induces extracellular signal-regulated kinase phosphorylation and cardiomyocyte hypertrophy

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