Inhibitory actions of the NRG-1/ErbB4 pathway in macrophages during tissue fibrosis in the heart, skin, and lung

The neuregulin-1 (NRG-1)/receptor tyrosine-protein kinase erbB (ErbB) system is an endothelium-controlled paracrine system modulating cardiac performance and adaptation. Recent studies have indicated that NRG-1 has antifibrotic effects in the left ventricle, which were explained by direct actions on cardiac fibroblasts. However, the NRG-1/ErbB system also regulates the function of macrophages. In this study, we hypothesized that the antifibrotic effect of NRG-1 in the heart is at least partially mediated through inhibitory effects on macrophages. We also hypothesized that the antifibrotic effect of NRG-1 may be active in other organs, such as the skin and lung. First, in a mouse model of angiotensin II (ANG II)-induced myocardial hypertrophy and fibrosis, NRG-1 treatment (20 µg·kg−1·day−1 ip) significantly attenuated myocardial hypertrophy and fibrosis and improved passive ventricular stiffness (4 wk). Interestingly, 1 wk after exposure to ANG II, NRG-1 already attenuated myocardial macrophage infiltration and cytokine expression. Furthermore, mice with myeloid-specific deletion of the ErbB4 gene ( ErbB4F/FLysM-Cre+/−) showed an intensified myocardial fibrotic response to ANG II. Consistently, NRG-1 activated the ErbB4 receptor in isolated macrophages, inhibited phosphatidylinositide 3-kinase/Akt and STAT3 signaling pathways, and reduced the release of inflammatory cytokines. Further experiments showed that the antifibrotic and anti-inflammatory effects of NRG-1 were reproducible in mouse models of bleomycin-induced dermal and pulmonary fibrosis. Overall, this study demonstrates that the antifibrotic effect of NRG-1 in the heart is linked to anti-inflammatory activity NRG-1/ErbB4 signaling in macrophages. Second, this study shows that NRG-1 has antifibrotic and anti-inflammatory effects in organs other than the heart, such as the skin and lung. NEW & NOTEWORTHY Our study contributes to the understanding of the antifibrotic effect of neuregulin-1 during myocardial remodeling. Here, we show that the antifibrotic effect of neuregulin-1 is at least partially mediated through anti-inflammatory activity, linked to receptor tyrosine-protein kinase erbB-4 activation in macrophages. Furthermore, we show that this effect is also present outside the heart. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/nrg-1-inhibits-macrophage-activation-during-tissue-fibrosis/ .

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Anti-Inflammatory Activity of Populus deltoides Leaf Extract via Modulating NF-κB and p38/JNK Pathways

International Journal of Molecular Sciences ◽

10.3390/ijms19123746 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3746 ◽

Cited By ~ 5

Author(s):

Ye Jeong ◽

Mi-Young Lee

Keyword(s):

Nitric Oxide ◽

Protein Kinase ◽

Leaf Extract ◽

Populus Deltoides ◽

Nuclear Translocation ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Inflammatory Activity ◽

No Production ◽

Anti Inflammatory

Populus deltoides, known as eastern cottonwood, has been commonly used as a medicinal plant. The aim of the present study was to investigate the mechanism underlying the anti-inflammatory activity of P. deltoides leaf extract (PLE). PLE effectively inhibited the expression of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, but not that of cyclooxygenase-2 (COX-2) and prostaglandin E2. Proinflammatory tumor necrosis factor alpha (TNF-α) levels were also reduced by the extract. PLE inhibited the phosphorylation of nuclear factor-kappa B (NF-κB) and inhibitor of Kappa Bα (IκBα), and blunted LPS-triggered enhanced nuclear translocation of NF-κB p65. In mitogen-activated protein kinase (MAPK) signaling, PLE effectively decreased the phosphorylation of p38 and c-Jun N-terminal protein kinase (JNK), but not of extracellular signal-regulated kinase 1/2 (ERK1/2). Taken together, these results suggest that anti-inflammatory activity of P. deltoides leaf extract might be driven by iNOS and NO inhibition mediated by modulation of the NF-κB and p38/JNK signaling pathways.

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Angiotensin (ang) 1-7 inhibits ang II-induced atrial fibrosis through regulating the interaction of proto-oncogene tyrosine-protein kinase Src (c-Src) and Src homology region 2 domain-containing phosphatase-1 (SHP-1))

Bioengineered ◽

10.1080/21655979.2021.1967035 ◽

2021 ◽

Vol 12 (2) ◽

pp. 10823-10836

Author(s):

Li Lu ◽

Li Cao ◽

Yihao Liu ◽

Yunlin Chen ◽

Jinqi Fan ◽

...

Keyword(s):

Protein Kinase ◽

Ang Ii ◽

Atrial Fibrosis ◽

Homology Region ◽

Tyrosine Protein Kinase ◽

Src Homology

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Propofol Depresses Angiotensin II–induced Cell Proliferation in Rat Cardiac Fibroblasts

Anesthesiology ◽

10.1097/01.anes.0000365960.74268.21 ◽

2010 ◽

Vol 112 (1) ◽

pp. 108-118 ◽

Cited By ~ 15

Author(s):

Tzu-Hurng Cheng ◽

Yuk-Man Leung ◽

Chi-Wai Cheung ◽

Cheng-Hsien Chen ◽

Yen-Ling Chen ◽

...

Keyword(s):

Nitric Oxide ◽

Cell Proliferation ◽

Protein Kinase ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Protein Kinase B ◽

Cardiac Fibroblasts ◽

Ang Ii ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Background Propofol may have beneficial effects on the prevention of angiotensin II (Ang II)-induced cardiac fibroblast proliferation via its antioxidative properties. The authors hypothesized that propofol may alter Ang II-induced cell proliferation and aimed to identify the putative underlying signaling pathways in rat cardiac fibroblasts. Methods Cultured rat cardiac fibroblasts were pretreated with propofol then stimulated with Ang II; cell proliferation and endothelin-1 gene expression were examined. The effect of propofol on Ang II-induced nicotinamide adenine dinucleotide phosphate-oxidase activity, reactive oxygen species formation, extracellular signal-regulated kinase phosphorylation, and activator protein 1-mediated reporter activity were also examined. The effect of propofol on nitric oxide production and protein kinase B and endothelial nitric oxide synthase phosphorylations were also tested to elucidate the intracellular mechanism of propofol in proliferation. Results Ang II (100 nm) increased cell proliferation and endothelin-1 expression, which were partially inhibited by propofol (10 or 30 microm). Propofol also inhibited Ang II-increased nicotinamide adenine dinucleotide phosphate-oxidase activity, reactive oxygen species formation, extracellular signal-regulated kinase phosphorylation, and activator protein 1-mediated reporter activity. Propofol was also found to increase nitric oxide generation and protein kinase B and nitric oxide synthase phosphorylations. Nitric oxide synthase inhibitor (N-nitro-L-arginine methylester) and the short interfering RNA transfection for protein kinase B or endothelial nitric oxide synthase markedly attenuated the inhibitory effect of propofol on Ang II-induced cell proliferation. Conclusions The authors' results suggest that propofol prevents cardiac fibroblast proliferation by interfering with the generation of reactive oxygen species and involves the activation of the protein kinase B-endothelial nitric oxide synthase-nitric oxide pathway.

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Genetic study of neuregulin 1 and receptor tyrosine-protein kinase erbB-4 in tardive dyskinesia

The World Journal of Biological Psychiatry ◽

10.1080/15622975.2017.1301681 ◽

2017 ◽

Vol 20 (1) ◽

pp. 91-95 ◽

Cited By ~ 6

Author(s):

Clement C. Zai ◽

Arun K. Tiwari ◽

Nabilah I. Chowdhury ◽

Zeynep Yilmaz ◽

Vincenzo de Luca ◽

...

Keyword(s):

Protein Kinase ◽

Tardive Dyskinesia ◽

Genetic Study ◽

Neuregulin 1 ◽

Tyrosine Protein Kinase

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Anti-inflammatory activity of atractylenolide III through inhibition of nuclear factor-κB and mitogen-activated protein kinase pathways in mouse macrophages

Immunopharmacology and Immunotoxicology ◽

10.3109/08923973.2015.1122617 ◽

2015 ◽

Vol 38 (2) ◽

pp. 98-102 ◽

Cited By ~ 20

Author(s):

Guang-Quan Ji ◽

Ren-Qiong Chen ◽

Ling Wang

Keyword(s):

Protein Kinase ◽

Nuclear Factor Κb ◽

Mitogen Activated Protein Kinase ◽

Inflammatory Activity ◽

Nuclear Factor ◽

Mouse Macrophages ◽

Mitogen Activated Protein ◽

Anti Inflammatory ◽

Atractylenolide Iii

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Oral, anti-inflammatory activity of a potent, selective, protein kinase C inhibitor

Agents and Actions ◽

10.1007/bf01987894 ◽

1992 ◽

Vol 37 (1-2) ◽

pp. 85-89 ◽

Cited By ~ 6

Author(s):

M. J. Mulqueen ◽

D. Bradshaw ◽

P. D. Davis ◽

L. Elliott ◽

T. A. Griffiths ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Inflammatory Activity ◽

Kinase C ◽

Protein Kinase C Inhibitor ◽

Anti Inflammatory

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Anti-inflammatory Activity of Methylene Chloride Fraction From Glehnia littoralis Extract via Suppression of NF-κB and Mitogen-Activated Protein Kinase Activity

Journal of Pharmacological Sciences ◽

10.1254/jphs.09168fp ◽

2010 ◽

Vol 112 (1) ◽

pp. 46-55 ◽

Cited By ~ 24

Author(s):

Taesook Yoon ◽

Myeong Sook Cheon ◽

A Yeong Lee ◽

Do Yeon Lee ◽

Byeong Cheol Moon ◽

...

Keyword(s):

Protein Kinase ◽

Kinase Activity ◽

Methylene Chloride ◽

Mitogen Activated Protein Kinase ◽

Inflammatory Activity ◽

Protein Kinase Activity ◽

Glehnia Littoralis ◽

Mitogen Activated Protein ◽

Anti Inflammatory ◽

Methylene Chloride Fraction

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Oral anti-inflammatory activity of a potent, selective, protein kinase C inhibitor

International Journal of Immunopharmacology ◽

10.1016/0192-0561(91)90271-8 ◽

1991 ◽

Vol 13 (6) ◽

pp. 749 ◽

Cited By ~ 1

Author(s):

D. Bradshaw ◽

M. Mulqueen ◽

E. Lewis ◽

J. Bishop ◽

A. Greenham ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Inflammatory Activity ◽

Kinase C ◽

Protein Kinase C Inhibitor ◽

Anti Inflammatory

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Protein kinase C contributes to desensitization of ANG II signaling in adult rat cardiac fibroblasts

AJP Cell Physiology ◽

10.1152/ajpcell.2000.279.6.c1978 ◽

2000 ◽

Vol 279 (6) ◽

pp. C1978-C1985 ◽

Cited By ~ 12

Author(s):

J. Gary Meszaros ◽

Robert Raphael ◽

Francisco M. Lio ◽

Laurence L. Brunton

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Time Course ◽

Inositol Phosphate ◽

Cardiac Fibroblasts ◽

Primary Cultures ◽

Ang Ii ◽

Adult Rat ◽

Kinase C ◽

Gf 109203X

We have studied Gq-linked ANG II signaling [inositol phosphate (IP) accumulation, Ca2+ mobilization] in primary cultures of rat cardiac fibroblasts (CFs) and have found that ANG II initiates a protein kinase C (PKC)-mediated negative feedback loop that rapidly terminates the ANG II response. Pharmacological inhibition of PKC by staurosporine and GF-109203X doubled IP production over that achieved in response to ANG II alone. Inhibition of PKC also led to larger Ca2+ transients in response to ANG II, suggesting that Ca2+ mobilization was proportional to Gq-phospholipase C-IP3 activity under the conditions studied. Depletion of cellular PKC by overnight treatment with phorbol 12-myristate 13-acetate (PMA) similarly augmented ANG II-induced IP production. Acute activation of PKC by PMA halved IP formation, with an EC50≈1 nM; 4α-PMA was inactive. Time course data demonstrated that ANG II-mediated IP production fully desensitized within 30 s; PKC inhibition reduced the rate and extent of this desensitization. In cells desensitized to ANG II, a purinergic agonist still mobilized intracellular Ca2+, indicating that desensitization was homologous. The ANG II-induced Ca2+ signal was fully resensitized within 30 min. The data demonstrate that a large portion of the IP-Ca2+ responses of rat CFs to ANG II are short-lived because of rapid, PKC-mediated desensitization.

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