scholarly journals Angiotensin II deteriorates advanced atherosclerosis by promoting MerTK cleavage and impairing efferocytosis through the AT1R/ROS/p38 MAPK/ADAM17 pathway

2019 ◽  
Vol 317 (4) ◽  
pp. C776-C787 ◽  
Author(s):  
Yan Zhang ◽  
Ying Wang ◽  
Dong Zhou ◽  
Li-Sha Zhang ◽  
Fu-Xue Deng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Atherosclerotic Lesion ◽  
Serum Levels ◽  
Soluble Form ◽  
Ang Ii ◽  
Double Positive ◽  
Mapk Phosphorylation ◽  
Coronary Syndrome

Vulnerable plaques in advanced atherosclerosis have defective efferocytosis. The role of ANG II in the progression of atherosclerosis is not fully understood. Herein, we investigated the effects and the underlying mechanisms of ANG II on macrophage efferocytosis in advanced atherosclerosis. ANG II decreased the surface expression of Mer tyrosine kinase (MerTK) in macrophages through a disintegrin and metalloproteinase17 (ADAM17)-mediated shedding of the soluble form of MerTK (sMer) in the medium, which led to efferocytosis suppression. ANG II-activated ADAM17 required reactive oxygen species (ROS) and p38 MAPK phosphorylation. Selective angiotensin II type 1 receptor (AT1R) blocker losartan suppressed ROS production, and ROS scavenger N-acetyl-l-cysteine (NAC) prevented p38 MAPK phosphorylation. In addition, mutant MERTKΔ483-488 was resistant to ANG II-induced MerTK shedding and efferocytosis suppression. The advanced atherosclerosis model that is characterized by larger necrotic cores, and less collagen content was established by feeding apolipoprotein E knockout (ApoE−/−) mice with a high-fat diet for 16 wk. NAC and losartan oral administration prevented atherosclerotic lesion progression. Meanwhile, the inefficient efferocytosis represented by decreased macrophage-associated apoptotic cells and decreased MerTK+CD68+double-positive macrophages in advanced atherosclerosis were prevented by losartan and NAC. Additionally, the serum levels of sMer were increased and positively correlated with the upregulated levels of ANG II in acute coronary syndrome (ACS) patients. In conclusion, ANG II promotes MerTK shedding via AT1R/ROS/p38 MAPK/ADAM17 pathway in macrophages, which led to defective efferocytosis and atherosclerosis progression. Defining the molecular mechanisms of defective efferocytosis may provide a promising prognosis and therapy for ACS patients.

Angiotensin (1-7) prevents angiotensin II-induced nociceptive behaviour via inhibition of p38 MAPK phosphorylation mediated through spinal Mas receptors in mice

2014 ◽  
Vol 18 (10) ◽  
pp. 1471-1479 ◽  
Author(s):  
W. Nemoto ◽  
Y. Ogata ◽  
O. Nakagawasai ◽  
F. Yaoita ◽  
T. Tadano ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
P38 Mapk ◽  
Mapk Phosphorylation ◽  
Nociceptive Behaviour

scholarly journals Thromboplasminflammation in COVID-19 Coagulopathy: Three Viewpoints for Diagnostic and Therapeutic Strategies

2021 ◽  
Vol 12 ◽  
Author(s):  
Satoshi Gando ◽  
Takeshi Wada
Keyword(s):  
Angiotensin Ii ◽  
Plasminogen Activator ◽  
Thrombin Generation ◽  
Molecular Mechanisms ◽  
Endothelial Injury ◽  
Neutrophil Extracellular Trap ◽  
Tissue Type ◽  
Clear Understanding ◽  
Factor Xii ◽  
Ang Ii

Thromboplasminflammation in coronavirus disease 2019 (COVID-19) coagulopathy consists of angiotensin II (Ang II)-induced coagulopathy, activated factor XII (FXIIa)- and kallikrein, kinin system-enhanced fibrinolysis, and disseminated intravascular coagulation (DIC). All three conditions induce systemic inflammation via each pathomechanism-developed production of inflammatory cytokines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) downregulates angiotensin-converting enzyme 2, leading to an increase in Ang II levels. Ang II-induced coagulopathy comprising platelet activation, thrombin generation, plasminogen activator inhibitor-1 expression and endothelial injury causes thrombosis via the angiotensin II type 1 receptor. SARS-CoV-2 RNA and neutrophil extracellular trap (NET) DNA activate FXII, resulting in plasmin generation through FXIIa- and kallikrein-mediated plasminogen conversion to plasmin and bradykinin-induced tissue-type plasminogen activator release from the endothelium via the kinin B2 receptor. NETs induce immunothrombosis at the site of infection (lungs), through histone- and DNA-mediated thrombin generation, insufficient anticoagulation control, and inhibition of fibrinolysis. However, if the infection is sufficiently severe, immunothrombosis disseminates into the systemic circulation, and DIC, which is associated with the endothelial injury, occurs. Inflammation, and serine protease networks of coagulation and fibrinolysis, militate each other through complement pathways, which exacerbates three pathologies of COVID-19 coagulopathy. COVID-19 coagulopathy causes microvascular thrombosis and bleeding, resulting in multiple organ dysfunction and death in critically ill patients. Treatment targets for improving the prognosis of COVID-19 coagulopathy include thrombin, plasmin, and inflammation, and SARS-CoV-2 infection. Several drugs are candidates for controlling these conditions; however, further advances are required to establish robust treatments based on a clear understanding of molecular mechanisms of COVID-19 coagulopathy.

scholarly journals The TGFβ-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1

Open Biology ◽  
2013 ◽  
Vol 3 (6) ◽  
pp. 130067 ◽  
Author(s):  
Gopal P. Sapkota
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Phosphorylation ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein

The signalling pathways downstream of the transforming growth factor beta (TGFβ) family of cytokines play critical roles in all aspects of cellular homeostasis. The phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in TGFβ-induced epithelial-to-mesenchymal transition and apoptosis. The precise molecular mechanisms by which TGFβ cytokines induce the phosphorylation and activation of p38 MAPK are unclear. In this study, I demonstrate that TGFβ-activated kinase 1 (TAK1/MAP3K7) does not play a role in the TGFβ-induced phosphorylation and activation of p38 MAPK in MEFs and HaCaT keratinocytes. Instead, RNAi -mediated depletion of MAP3K4 and MAP3K10 results in the inhibition of the TGFβ-induced p38 MAPK phosphorylation. Furthermore, the depletion of MAP3K10 from cells homozygously knocked-in with a catalytically inactive mutant of MAP3K4 completely abolishes the TGFβ-induced phosphorylation of p38 MAPK, implying that among MAP3Ks, MAP3K4 and MAP3K10 are sufficient for mediating the TGFβ-induced activation of p38 MAPK.

scholarly journals IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Hao Chai ◽  
ZhongHao Tao ◽  
YongChao Qi ◽  
HaoYu Qi ◽  
Wen Chen ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Ang Ii ◽  
Elastin Degradation ◽  
Maximal Diameter ◽  
Abdominal Aortic ◽  
Primary Mouse

Abdominal aortic aneurysm (AAA) is a vascular disorder that is considered a chronic inflammatory disease. However, the precise molecular mechanisms involved in AAA have not been fully elucidated. Recently, significant progress has been made in understanding the function and mechanism of action of inhibitor of kappa B kinase epsilon (IKKε) in inflammatory and metabolic diseases. The angiotensin II- (Ang II-) induced or pharmacological inhibitors were established to test the effects of IKKε on AAA in vivo. After mice were continuously stimulated with Ang II for 28 days, morphologically, we found that knockout of IKKε reduced AAA formation and drastically reduced maximal diameter and severity. We also observed a decrease in elastin degradation and medial destruction, which were independent of systolic blood pressure or plasma cholesterol concentrations. Western blot analyses and immunohistochemical staining were carried out to measure IKKε expression in AAA tissues and cell lines. AAA phenotype of mice was measured by ultrasound and biochemical indexes. In zymography, immunohistology staining, immunofluorescence staining, and reactive oxygen species (ROS) analysis, TUNEL assay was used to examine the effects of IKKε on AAA progression in AAA mice. IKKε deficiency significantly inhibited inflammatory macrophage infiltration, matrix metalloproteinase (MMP) activity, ROS production, and vascular smooth muscle cell (VSMC) apoptosis. We used primary mouse aortic VSMC isolated from apolipoprotein E (Apoe) −/− and Apoe−/−IKKε−/− mice. Mechanistically, IKKε deficiency blunted the activation of the ERK1/2 pathway. The IKKε inhibitor, amlexanox, has the same impact in AAA. Our results demonstrate a critical role of IKKε in AAA formation induced by Ang II in Apoe−/− mice. Targeting IKKε may constitute a novel therapeutic strategy to prevent AAA progression.

scholarly journals Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

2016 ◽  
Vol 39 (1) ◽  
pp. 13-32 ◽  
Author(s):  
Yuanyuan Ji ◽  
Zhidong Wang ◽  
Zongfang Li ◽  
Aijun Zhang ◽  
Yaofeng Jin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Angiotensin Ii ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Hepatocyte Proliferation ◽  
Nuclear Antigen ◽  
Ang Ii ◽  
Hcc Cells

Background/Aims: The pathogenesis of hepatocellular carcinoma (HCC) is mainly characterized by persistent cycles of liver injury, inflammation, and compensatory hepatocyte proliferation. Angiotensin II (Ang II) behaves as an endogenous pro-inflammatory molecule playing a significant role in HCC, however, the molecular link between Ang II, proliferation and inflammation remains unclear. Methods: Human HCC cell lines (HepG-2, SMMC-7721, MHCC97-H) were incubated with Ang II at the indicated concentrations for 24, 48, 72 h. MTT, BrdU ELISA, plate colony formation assay, immunohistochemistry, ELISA, small-interfering RNA(siRNA) transfection, quantitative real-time PCR and western blot were applied to assess their functional, morphological and molecular mechanisms in HCC cell lines. Results: High expression of Ang II type 1 receptor (AT1) and low expression of AT2 in HCC cells and tissues were found. Next, Ang II could significantly enhance cell growth and proliferation. Albeit Ang II slightly increased the percentage of HCC cells in the G0/G1 phase using flow cytometry analysis, no statistically significant alterations were shown. Further studies suggested that Ang II could directly induce proliferation associated proteins C-myc and proliferating cell nuclear antigen (PCNA) expressions, and inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) productions in HCC cells. Interestingly, blocking AT1 and AT1 siRNA evidently inhibited Ang II-induced cell proliferation and inflammatory responses in HCC cells. More importantly, these effects may be mediated by AT1/PKC/NF-κB signaling pathway in HCC cell lines. Conclusions: The results propose that Ang II/AT1/PKC/NF-κB signaling pathway is necessary for proliferation and inflammation of HCC cells, which increases our understanding of the pathogenesis and provides clues for developing new strategies against Ang II-related progress of HCC.

scholarly journals Angiotensin II Suppresses Rev-erbα Expression in THP-1 Macrophages via the Ang II Type 1 Receptor/Liver X Receptor α Pathway

2018 ◽  
Vol 46 (1) ◽  
pp. 303-313 ◽  
Author(s):  
Shipeng Wang ◽  
Xia Gu ◽  
Qi Zhang ◽  
Xiling Zhang ◽  
Yilan Li ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Atherosclerotic Lesion ◽  
Liver X Receptor ◽  
Time Dependent ◽  
Dependent Manner ◽  
Ang Ii ◽  
Raw264.7 Macrophages ◽  
Liver X Receptor Α

Background/Aims: Angiotensin II (Ang II) regulates the expression of some core clock genes; excess Ang II leads to atherosclerosis advancement. Macrophage Rev-erbα mediates clockwork and inflammation, and plays a role in atherosclerotic lesion progression. However, the role of Ang II in regulating Rev-erbα expression in macrophages remains unclarified. Methods: We induced THP-1 macrophages by phorbol 12-myristate 13-acetate and investigated the effect of Ang II on Rev-erbα expression via real-time polymerase chain reaction, western blotting and small interfering RNA (siRNA) techniques. The cytotoxicity of the Rev-erbα agonist SR9009 was analyzed using a (3-[4,5-dimethylthiazol-2-yl])-2,5- diphenyltetrazolium bromide assay. Results: Ang II suppressed Rev-erbα mRNA and protein expression in THP-1 macrophages in a dose and time dependent manner. This effect was mediated via Ang II type 1 receptor (AT1R), and not Ang II type 2 receptor or peroxisome proliferator-activated receptor γ (PPARγ). Consistent with Rev-erbα expression regulated by Ang II, the liver X receptor α (LXRα) protein expression was downregulated in a time-dependent manner after Ang II treatment. The activation or silence of LXRα significantly increased or decreased Rev-erbα expression regulated by Ang II, respectively. This suggests that LXRα is involved in the effect of Ang II on Rev-erbα expression. MMP-9 mRNA expressions were significantly suppressed by SR9009 in THP-1 and RAW264.7 macrophages; moreover, SR9009-treatment significantly reduced Ang II–induced MMP-9 protein expressions in two types of macrophages. Conclusion: Ang II downregulates Rev-erbα expression in THP-1 macrophages via the AT1R/LXRα pathway.

scholarly journals Irbesartan, an angiotensin II type 1 receptor blocker, inhibits colitis-associated tumourigenesis by blocking the MCP-1/CCR2 pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kensuke Hachiya ◽  
Masahiro Masuya ◽  
Naoki Kuroda ◽  
Misao Yoneda ◽  
Junya Tsuboi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Angiotensin Ii ◽  
Molecular Mechanisms ◽  
Experimental Colitis ◽  
Sodium Sulphate ◽  
Receptor Blocker ◽  
Ang Ii ◽  
Monocyte Chemoattractant Protein 1 ◽  
Intestinal Fibrosis

AbstractThe introduction of anti-inflammatory therapies has enabled substantial improvement of disease activity in patients with inflammatory bowel diseases (IBD). However, IBD can lead to serious complications such as intestinal fibrosis and colorectal cancer. Therefore, novel therapies reducing the development of these complications are needed. Angiotensin II (Ang II) promotes tissue inflammation by stimulating the production of monocyte chemoattractant protein-1 (MCP-1) or proinflammatory cytokines. It plays a pivotal role in IBD progression. Although blockade of Ang II has been reported to ameliorate experimental colitis and reduce colorectal cancer risk, the cellular and molecular mechanisms remain poorly understood. Our previous work showed that irbesartan, an Ang II type 1 receptor blocker, reduced the number of C–C chemokine receptor 2-positive (CCR2+) monocytic cells in the inflamed pancreas. This study aimed to investigate the possible antifibrotic and antitumour effects of irbesartan using the azoxymethane/dextran sodium sulphate mouse model. Irbesartan suppressed MCP-1 production and the accumulation of Ly6C+CCR2+ monocytes and fibrocytes in the inflamed colon, downregulated the expression of type 1 collagen and matrix metalloproteinase 9 and inhibited the development of intestinal fibrosis and tumours. Our observations suggest that blocking the MCP-1/CCR2 pathway using irbesartan might be beneficial in preventing colitis-associated colon tumours.

Abstract 1311: Bone Marrow Angiotensin II Type 1 Receptor Augments Atherosclerosis by Promoting Monocyte/Macrophage Lineage Differentiation from Hematopoietic Stem Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yoshinori Tsubakimoto ◽  
Hiroyuki Yamada ◽  
Hirokazu Yokoi ◽  
Hiroki Takata ◽  
Hiroyuki Kawahito ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Angiotensin Ii ◽  
Hematopoietic Stem Cells ◽  
Atherosclerotic Lesion ◽  
Ang Ii ◽  
Hematopoietic Stem ◽  
Apoe Ko Mice ◽  
Apoe Ko

[BACKGROUND] The angiotensin II (Ang II) type 1 (AT 1 ) receptor is crucially involved in atherogenesis, but bone marrow (BM) AT 1 -mediated proatherogenic action remains undefined- . [METHOD AND RESULT] BM-derived mononuclear cells (BM-MNCs) more abundantly express AT 1 than VSMCs (2.2 fold) with similar affinities to Ang II. BM cells in 8-week-old apoE-deficient −/− ) or wild-type (Agtr1 + / + ) cells. Four (apoE-KO) mice were replaced with AT 1 -deficient (Agtr1 weeks after the initiation of western diet and Ang II infusion (500ng/kg/min), atherosclerotic lesion area in aortic root was examined. ApoE-KO mice reconstituted with Agtr1 −/− marrow (apoE-KO/BM-Agtr1 −/− ) showed a significant reduction in atherosclerotic lesions compared with apoE-KO/BM-Agtr1 + / + mice (55%, P <0.05). The accumulation of macrophages was attenuated in apoE-KO/BM-Agtr1 −/− mice (55%, P <0.05), concomitant with a decrease in the number of circulating Ly-6C hi monocytes (76%, P <0.01). The numbers of circulating CCR2 + and CX3CR1 + monocytes were also reduced in apoE-KO/BM-Agtr1 −/− mice (87±16 vs 298±66; CCR2 + monocyte, 72±12 vs 550±119 cells/μl; CX3CR1 + monocyte, respectively, P <0.01). Furthermore, the number of macrophage progenitor cells defined by M-CSF stimulated macrophage colony-forming unit was markedly reduced by 82 % (p<0.01) in Agtr1 −/− compared with Agtr1 + / + mice. We next examined the effect of BM-AT 1 on the number of hematopoietic stem cells (HSCs), common myeloid progenitors (CMP), and granulocyte/macrophage progenitors (GMP) to determine at which point of the lineage pathway, BM-AT 1 is involved. The number of HSCs did not differ between the two groups (3.6±0.8 vs 2.9±0.6 × 10 3 cells/tibia, P =n.s.), whereas the numbers of CMP and GMP were much lower in apoE-KO/BM-Agtr1 −/− mice (4.7±0.7 vs 10.2±1.4 ×10 3 cells/tibia, 9.9±2.7 vs 20.2±2.8 × 10 3 cells/tibia, respectively, P <0.05). [CONCLUSION] BM-MNCs expressed the abundant densities of AT1, and AT1-mediated signals on BM-MNCs exaggerated atherosclerotic lesion development. BM-AT 1 is closely implicated in the differentiation of HSCs into macrophage progenitors and the behavior of monocytes/macrophages, indicating that BM-AT 1 could be a promising therapeutic target for the prevention of cardiovascular events.

scholarly journals Central SDF-1/CXCL12 expression and its cardiovascular and sympathetic effects: the role of angiotensin II, TNF-α, and MAP kinase signaling

2014 ◽  
Vol 307 (11) ◽  
pp. H1643-H1654 ◽  
Author(s):  
Shun-Guang Wei ◽  
Zhi-Hua Zhang ◽  
Yang Yu ◽  
Robert B. Felder
Keyword(s):  
Angiotensin Ii ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Ang Ii ◽  
Cxcl12 Expression ◽  
Tnf Α ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors ◽  
Stromal Cell Derived Factor

The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptors are expressed by neurons and glial cells in cardiovascular autonomic regions of the brain, including the hypothalamic paraventricular nucleus (PVN), and contribute to neurohumoral excitation in rats with ischemia-induced heart failure. The present study examined factors regulating the expression of SDF-1 in the PVN and mechanisms mediating its sympatho-excitatory effects. In urethane anesthetized rats, a 4-h intracerebroventricular (ICV) infusion of angiotensin II (ANG II) or tumor necrosis factor-α (TNF-α) in doses that increase mean blood pressure (MBP) and sympathetic drive increased the expression of SDF-1 in PVN. ICV administration of SDF-1 increased the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), JNK, and p38 MAPK in PVN, along with MBP, heart rate (HR), and renal sympathetic nerve activity (RSNA), but did not affect total p44/42 MAPK, JNK, and p38 MAPK levels. ICV pretreatment with the selective p44/42 MAPK inhibitor PD98059 prevented the SDF-1-induced increases in MBP, HR, and RSNA; ICV pretreatment with the selective JNK and p38 MAPK inhibitors attenuated but did not block these SDF-1-induced excitatory responses. ICV PD98059 also prevented the sympatho-excitatory response to bilateral PVN microinjections of SDF-1. ICV pretreatment with SDF-1 short-hairpin RNA significantly reduced ANG II- and TNF-α-induced phosphorylation of p44/42 MAPK in PVN. These findings identify TNF-α and ANG II as drivers of SDF-1 expression in PVN and suggest that the full expression of their cardiovascular and sympathetic effects depends upon SDF-1-mediated activation of p44/42 MAPK signaling.

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