ERK activation contributes to regulation of spontaneous contractile tone via superoxide anion in isolated rat aorta of angiotensin II-induced hypertension

Arteries from hypertensive animals and humans have increased spontaneous tone. Increased superoxide anion (superoxide) contributes to elevated blood pressure (BP) and spontaneous tone in hypertension. The association between the extracellular signaling-regulated kinase 1/2 (ERK1/2)-mitogen-activated protein kinase (MAPK) signaling pathway and generation of superoxide and spontaneous tone in isolated aorta was studied in angiotensin II (ANG II)-infused hypertensive (HT) rats. Systolic BP, phosphorylation of ERK, aortic superoxide formation, and aortic spontaneous tone were compared in sham normotensive and HT rats. Infusion of ANG II (0.5 mg·kg−1·day−1 for 6 days) significantly elevated the systolic BP ( P < 0.01). The phosphorylation of ERK1/2 vs. total ERK1/2 in thoracic aorta was enhanced, and superoxide was increased in the HT vs. the sham group ( P < 0.01). Spontaneous tone developed in the HT group, but not in the normotensive group. MAPK/ERK1/2 (MEK1/2)-ERK1/2 signaling pathway inhibitors, PD-98059 (10 μmol/l), and U-0126 (10 μmol/l), significantly reduced the phosphorylation of ERK1/2, superoxide generation ( P < 0.01), and spontaneous tone ( P < 0.01) in HT. These findings suggest that ANG II infusion induces the production of superoxide and spontaneous tone and that both are dependent on ERK-MAPK activation. In endothelium-denuded aorta, however, MEK1/2 inhibitors did not inhibit the spontaneous tone, even though they significantly reduced superoxide generation similar to endothelium-intact aorta. These data suggest that inhibition of ERK1/2 signaling pathway, via PD-98059 or U-0126, may regulate spontaneous tone in an endothelium-dependent manner. In conclusion, these findings support the importance of the ERK1/2 signaling pathway in modulating vascular oxidative stress and subsequently mediating spontaneous tone in HT.

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Potentiation of angiotensin II-stimulated vascular contraction by lithium

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.268.5.h2009 ◽

1995 ◽

Vol 268 (5) ◽

pp. H2009-H2016

Author(s):

M. E. Ullian ◽

L. G. Walsh ◽

K. C. Wong ◽

C. J. Allan

Keyword(s):

Angiotensin Ii ◽

Inositol Phosphate ◽

Cytosolic Calcium ◽

Rat Aorta ◽

Dependent Manner ◽

Ang Ii ◽

Concentration Dependent Manner ◽

Adrenergic Agents ◽

Phosphoinositide Signaling ◽

Protein Kinase C Inhibitor

Previous studies have suggested that lithium prolongs or enhances vascular contractions stimulated by alpha-adrenergic agents. The present study was performed to determine whether a similar phenomenon occurs with angiotensin II (ANG II)-stimulated contractions and whether this phenomenon results from interactions with the phosphoinositide signaling system. Contractions of rat aortic rings with 100 nM ANG II were 38% greater in the presence of 20 mM LiCl than in its absence (0.47 +/- 0.07 vs. 0.34 +/- 0.05 g tension/mg dry tissue wt, P < 0.01). The effects of lithium on inositol phosphate responses, diacylglycerol responses, and intracellular calcium concentration on single or repeated stimulations with ANG II were then examined in vascular smooth muscle cells cultured from rat aorta. Cells exposed twice to 100 nM ANG II contained 50% lower inositol trisphosphate levels (InsP3) and 10% lower diacylglycerol levels than cells exposed to ANG II only once. LiCl or lithium acetate abolished these desensitizations in a concentration-dependent manner. Similarly, InsP3 and diacylglycerol responses to a single exposure of ANG II were heightened by lithium (by 75 and 25%, respectively), and the duration of the responses was prolonged by lithium (5- and 2-fold, respectively). In contrast, ANG II-stimulated calcium transients were not enhanced or prolonged by lithium, nor was desensitization of ANG II-stimulated cytosolic calcium mobilization upon serial exposures abolished by lithium. When ring contraction studies were repeated in the presence of the protein kinase C inhibitor staurosporine (150 nM), lithium no longer potentiated ANG II contractions [0.38 +/- 0.03 (control) vs. 0.35 +/- 0.06 g tension/mg dry tissue wt (lithium)].(ABSTRACT TRUNCATED AT 250 WORDS)

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Aloesin Suppresses Cell Growth and Metastasis in Ovarian Cancer SKOV3 Cells through the Inhibition of the MAPK Signaling Pathway

Analytical Cellular Pathology ◽

10.1155/2017/8158254 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Li-qian Zhang ◽

Rong-wei Lv ◽

Xiang-dong Qu ◽

Xian-jun Chen ◽

Hong-sheng Lu ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Growth ◽

Signaling Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Migration And Invasion ◽

Therapeutic Drug ◽

Dependent Manner ◽

Skov3 Cells

Aloesin is an active constituent of the herb aloe vera and plays a crucial role in anti-inflammatory activity, ultraviolet protection, and antibacterium. We investigated the role and possible mechanisms of aloesin in the cell growth and metastasis of ovarian cancer. It was found that aloesin inhibited cell viability and cell clonality in a dose-dependent manner. It arrests the cell cycle at the S-phase and induced apoptosis in SKOV3 cells. In an in vivo experiment, it was observed that aloesin inhibited tumor growth. Moreover, it inhibited migration and invasion of cancer in SKOV3 cells. Interestingly, members from the mitogen-activated protein kinase (MAPK) signaling family became less phosphorylated as the aloesin dose increased. This suggests that aloesin exerts its anticancer effect through the MAPK signaling pathway. Our data also highlights the possibility of using aloesin as a novel therapeutic drug for ovarian cancer treatment.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00432.2014 ◽

2014 ◽

Vol 307 (11) ◽

pp. H1643-H1654 ◽

Cited By ~ 14

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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Adiponectin Interacts In-Vitro With Cementoblasts Influencing Cell Migration, Proliferation and Cementogenesis Partly Through the MAPK Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2020.585346 ◽

2020 ◽

Vol 11 ◽

Author(s):

Jiawen Yong ◽

Julia von Bremen ◽

Gisela Ruiz-Heiland ◽

Sabine Ruf

Keyword(s):

Cell Migration ◽

Signaling Pathway ◽

Intracellular Signaling ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Nodule Formation ◽

Mrna Levels ◽

Dependent Manner ◽

Alizarin Red

Current clinical evidences suggest that circulating Adipokines such as Adiponectin can influence the ratio of orthodontic tooth movement. We aimed to investigate the effect that Adiponectin has on cementoblasts (OCCM-30) and on the intracellular signaling molecules of Mitogen-activated protein kinase (MAPK). We demonstrated that OCCM-30 cells express AdipoR1 and AdipoR2. Alizarin Red S staining revealed that Adiponectin increases mineralized nodule formation and quantitative AP activity in a dose-dependent manner. Adiponectin up-regulates the mRNA levels of AP, BSP, OCN, OPG, Runx-2 as well as F-Spondin. Adiponectin also increases the migration and proliferation of OCCM-30 cells. Moreover, Adiponectin induces a transient activation of JNK, P38, ERK1/2 and promotes the phosphorylation of STAT1 and STAT3. The activation of Adiponectin-mediated migration and proliferation was attenuated after pharmacological inhibition of P38, ERK1/2 and JNK in different degrees, whereas mineralization was facilitated by MAPK inhibition in varying degrees. Based on our results, Adiponectin favorably affect OCCM-30 cell migration, proliferation as well as cementogenesis. One of the underlying mechanisms is the activation of MAPK signaling pathway.

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Circular RNA hsa_circ_0006117 Facilitates Pancreatic Cancer Progression by Regulating the miR-96-5p/KRAS/MAPK Signaling Pathway

Journal of Oncology ◽

10.1155/2021/9213205 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Tao Liu ◽

Lei Zhou ◽

Zhiwei He ◽

Yankun Chen ◽

Xueyi Jiang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Circular Rna ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Luciferase Reporter ◽

Molecular Characteristics ◽

Dependent Manner

Circular RNAs (circRNAs) play key roles in many malignant tumors, including pancreatic cancer (PC); however, whether circular RNA hsa_circ_0006117, a newly identified circRNA, has a role in PC has not been investigated. Here, in order to elucidate the role and potential molecular mechanisms of circRNAs, we utilized bioinformatic tolls to screen the differentially expressed circRNAs in PC. Subsequently, circular RNA hsa_circ_0006117 was identified as being highly expressed in PC tissues in a screen of two GEO datasets, which was further verified in PC cell lines and tissues. Then, its molecular characteristics were investigated using methods such as Sanger sequencing and fluorescence in situ hybridization (FISH). Functional experiments subsequently indicated that circular RNA hsa_circ_0006117 facilitated the malignant behaviors of PC cells, prompting that it plays an oncogenic role in PC. Moreover, we found that circular RNA hsa_circ_0006117 exerts its PC-promoting effects via activating the KRAS/mitogen-activated protein kinase (MAPK) signaling pathway. Through bioinformatics exploration and dual-luciferase reporter assays, miR-96-5p was identified as a downstream target of circular RNA hsa_circ_0006117. A series of assays confirmed that circular RNA hsa_circ_0006117 acted as a miR-96-5p sponge, thereby promoting the malignant features of PC in a miR-96-5p/KRAS axis-dependent manner. Taken together, our study indicated, for the first time, that the specifically highly expressed circular RNA hsa_circ_0006117 facilitates PC progression via the modulation of the miR-96-5p/KRAS/MAPK signaling pathway and might be a hopeful therapeutic target for PC.

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Small peptide PEP7 can decease Angiotensin II (Ang II) induced function through MAPK signaling pathway

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.936.1 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Jun Liu ◽

Dan Zhang ◽

Hong Ji ◽

Bilkish Bajaj ◽

Wei Zheng ◽

...

Keyword(s):

Angiotensin Ii ◽

Signaling Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Ang Ii ◽

Small Peptide

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Parkia speciosa Hassk. Empty Pod Extract Alleviates Angiotensin II-Induced Cardiomyocyte Hypertrophy in H9c2 Cells by Modulating the Ang II/ROS/NO Axis and MAPK Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.741623 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hawa Nordin Siti ◽

Juriyati Jalil ◽

Ahmad Yusof Asmadi ◽

Yusof Kamisah

Keyword(s):

Nitric Oxide ◽

Reactive Oxygen Species ◽

Angiotensin Ii ◽

Mapk Pathway ◽

Reactive Oxygen ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Cardiomyocyte Hypertrophy ◽

Oxygen Species ◽

Ang Ii

Cardiac hypertrophy is characteristic of heart failure in patients who have experienced cardiac remodeling. Many medicinal plants, including Parkia speciosa Hassk., have documented cardioprotective effects against such pathologies. This study investigated the activity of P. speciosa empty pod extract against cardiomyocyte hypertrophy in H9c2 cardiomyocytes exposed to angiotensin II (Ang II). In particular, its role in modulating the Ang II/reactive oxygen species/nitric oxide (Ang II/ROS/NO) axis and mitogen-activated protein kinase (MAPK) pathway was examined. Treatment with the extract (12.5, 25, and 50 μg/ml) prevented Ang II-induced increases in cell size, NADPH oxidase activity, B-type natriuretic peptide levels, and reactive oxygen species and reductions in superoxide dismutase activity. These were comparable to the effects of the valsartan positive control. However, the extract did not significantly ameliorate the effects of Ang II on inducible nitric oxide synthase activity and nitric oxide levels, while valsartan did confer such protection. Although the extract decreased the levels of phosphorylated extracellular signal-related kinase, p38, and c-Jun N-terminal kinase, valsartan only decreased phosphorylated c-Jun N-terminal kinase expression. Phytochemical screening identified the flavonoids rutin (1) and quercetin (2) in the extract. These findings suggest that P. speciosa empty pod extract protects against Ang II-induced cardiomyocyte hypertrophy, possibly by modulating the Ang II/ROS/NO axis and MAPK signaling pathway via a mechanism distinct from valsartan.

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Angiotensin II Influences Pre-mRNA Splicing Regulation by Enhancing RBM20 Transcription Through Activation of the MAPK/ELK1 Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms20205059 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5059 ◽

Cited By ~ 2

Author(s):

Hanfang Cai ◽

Chaoqun Zhu ◽

Zhilong Chen ◽

Rexiati Maimaiti ◽

Mingming Sun ◽

...

Keyword(s):

Angiotensin Ii ◽

Protein Kinase ◽

Rna Binding ◽

Mapk Signaling ◽

Mrna Splicing ◽

Mitogen Activated Protein Kinase ◽

Binding Motif ◽

Cardiac Diseases ◽

Ang Ii ◽

The Impact

RNA binding motif 20 (RBM20) is a key regulator of pre-mRNA splicing of titin and other genes that are associated with cardiac diseases. Hormones, like insulin, triiodothyronine (T3), and angiotensin II (Ang II), can regulate gene-splicing through RBM20, but the detailed mechanism remains unclear. This study was aimed at investigating the signaling mechanism by which hormones regulate pre-mRNA splicing through RBM20. We first examined the role of RBM20 in Z-, I-, and M-band titin splicing at different ages in wild type (WT) and RBM20 knockout (KO) rats using RT-PCR; we found that RBM20 is the predominant regulator of I-band titin splicing at all ages. Then we treated rats with propylthiouracil (PTU), T3, streptozotocin (STZ), and Ang II and evaluated the impact of these hormones on the splicing of titin, LIM domain binding 3 (Ldb3), calcium/calmodulin-dependent protein kinase II gamma (Camk2g), and triadin (Trdn). We determined the activation of mitogen-activated protein kinase (MAPK) signaling in primary cardiomyocytes treated with insulin, T3, and Ang II using western blotting; MAPK signaling was activated and RBM20 expression increased after treatment. Two downstream transcriptional factors c-jun and ETS Transcription Factor (ELK1) can bind the promoter of RBM20. A dual-luciferase activity assay revealed that Ang II, but not insulin and T3, can trigger ELK1 and thus promote transcription of RBM20. This study revealed that Ang II can trigger ELK1 through activation of MAPK signaling by enhancing RBM20 expression which regulates pre-mRNA splicing. Our study provides a potential therapeutic target for the treatment of cardiac diseases in RBM20-mediated pre-mRNA splicing.

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Flavopereirine Inhibits Autophagy via the AKT/p38 MAPK Signaling Pathway in MDA-MB-231 Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21155362 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5362

Author(s):

Ming-Shan Chen ◽

Hsuan-Te Yeh ◽

Yi-Zhen Li ◽

Wen-Chun Lin ◽

Ying-Ray Lee ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

P38 Mapk ◽

Mammalian Target Of Rapamycin ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Akt Phosphorylation

Autophagy is a potential target for the treatment of triple negative breast cancer (TNBC). Because of a lack of targeted therapies for TNBC, it is vital to find optimal agents that avoid chemoresistance and metastasis. Flavopereirine has anti-proliferation ability in cancer cells, but whether it regulates autophagy in breast cancer cells remains unclear. A Premo™ Tandem Autophagy Sensor Kit was used to image the stage at which flavopereirine affects autophagy by confocal microscopy. A plasmid that constitutively expresses p-AKT and siRNA targeting p38 mitogen-activated protein kinase (MAPK) was used to confirm the related signaling pathways by Western blot. We found that flavopereirine induced microtubule-associated protein 1 light chain 3 (LC3)-II accumulation in a dose- and time-dependent manner in MDA-MB-231 cells. Confocal florescent images showed that flavopereirine blocked autophagosome fusion with lysosomes. Western blotting showed that flavopereirine directly suppressed p-AKT levels and mammalian target of rapamycin (mTOR) translation. Recovery of AKT phosphorylation decreased the level of p-p38 MAPK and LC3-II, but not mTOR. Moreover, flavopereirine-induced LC3-II accumulation was partially reduced in MDA-MB-231 cells that were transfected with p38 MAPK siRNA. Overall, flavopereirine blocked autophagy via LC3-II accumulation in autophagosomes, which was mediated by the AKT/p38 MAPK signaling pathway.

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