scholarly journals Specific role of the extracellular signal-regulated kinase pathway in angiotensin II-induced cardiac hypertrophy in vitro

2000 ◽  
Vol 347 (1) ◽  
pp. 275-284 ◽  
Author(s):  
Hiroki AOKI ◽  
Mary RICHMOND ◽  
Seigo IZUMO ◽  
Junichi SADOSHIMA
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Specific Inhibitor ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Specific Response ◽  
Erk Pathway ◽  
Ang Ii ◽  
Extracellular Signal

Although MAP (mitogen-activated protein) kinases are implicated in cell proliferation and differentiation in many cell types, the role of MAP kinases in cardiac hypertrophy remains unclear. We examined the role of extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAP kinase in angiotensin II (Ang II)-induced hypertrophy compared with phenylephrine-induced hypertrophy in neonatal rat cardiac myocytes. Both Ang II and phenylephrine activated ERKs to a similar extent, whereas phenylephrine caused stronger and more sustained activation of JNK and p38 than Ang II. PD98059, a specific inhibitor of MAPK/ERK kinase (MEK),inhibited Ang II-induced, but not phenylephrine-induced, expression of atrial natriuretic factor (ANF) at both the mRNA and polypeptide levels. SB203580, a specific inhibitor of p38 and some JNK isoforms, did not show significant effects on ANF expression induced by Ang II or phenylephrine. Although PD98059 and dominant-negative MEK1 blocked Ang II-induced activation of the ANF promoter, SB203580 or dominant-negative MEK kinase 1 (MEKK1) showed no effect. Phenylephrine-induced ANF promoter activation was significantly inhibited by SB203580 and dominant-negative MEKK1, but not by PD98059 or dominant-negative MEK1. Dominant-negative Ras inhibited both ERK activation and ANF up-regulation by Ang II, whereas constitutively active forms of Ras and MEK were sufficient to activate the ANF promoter. Dominant-negative Ras also partly inhibited the phenylephrine-induced activation of ANF promoter. PD98059 did not affect other markers of Ang II-induced hypertrophy, such as skeletal α-actin and c-fos expression, increases in the rate of protein synthesis or rapid sarcomeric actin organization. These results suggest that Ang II uses ERK for ANF expression, whereas phenylephrine uses other pathways. The Ras/ERK pathway selectively mediates ANF expression in various phenotypes observed in Ang II-induced hypertrophy. The ERK pathway mediates an agonist-specific and phenotype-specific response in cardiac hypertrophy.

Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy

2006 ◽  
Vol 26 (3) ◽  
pp. 180-191 ◽  
Author(s):  
Shawn D. Hingtgen ◽  
Xin Tian ◽  
Jusan Yang ◽  
Shannon M. Dunlay ◽  
Andrew S. Peek ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Dominant Negative ◽  
Time Dependent ◽  
Neonatal Rat ◽  
Signaling Cascade ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Akt Activation

Angiotensin II (ANG II) has profound effects on the development and progression of pathological cardiac hypertrophy; however, the intracellular signaling mechanisms are not fully understood. In this study, we used genetic tools to test the hypothesis that increased formation of superoxide (O2−·) radicals from a Rac1-regulated Nox2-containing NADPH oxidase is a key upstream mediator of ANG II-induced activation of serine-threonine kinase Akt, and that this signaling cascade plays a crucial role in ANG II-dependent cardiomyocyte hypertrophy. ANG II caused a significant time-dependent increase in Rac1 activation and O2−· production in primary neonatal rat cardiomyocytes, and these responses were abolished by adenoviral (Ad)-mediated expression of a dominant-negative Rac1 (AdN17Rac1) or cytoplasmic Cu/ZnSOD (AdCu/ZnSOD). Moreover, both AdN17Rac1 and AdCu/ZnSOD significantly attenuated ANG II-stimulated increases in cardiomyocyte size. Quantitative real-time PCR analysis demonstrated that Nox2 is the homolog expressed at highest levels in primary neonatal cardiomyocytes, and small interference RNA (siRNA) directed against it selectively decreased Nox2 expression by >95% and abolished both ANG II-induced O2−· generation and cardiomyocyte hypertrophy. Finally, ANG II caused a time-dependent increase in Akt activity via activation of AT1 receptors, and this response was abolished by Ad-mediated expression of cytosolic human O2−· dismutase (AdCu/ZnSOD). Furthermore, pretreatment of cardiomyocytes with dominant-negative Akt (AdDNAkt) abolished ANG II-induced cellular hypertrophy. These findings suggest that O2−· generated by a Nox2-containing NADPH oxidase is a central mediator of ANG II-induced Akt activation and cardiomyocyte hypertrophy, and that dysregulation of this signaling cascade may play an important role in cardiac hypertrophy.

RPC6 Up-Regulation in Ang II-Induced Podocyte Apoptosis Might Result from ERK Activation and NF-κB Translocation

2009 ◽  
Vol 234 (9) ◽  
pp. 1029-1036 ◽  
Author(s):  
Han Zhang ◽  
Jie Ding ◽  
Qingfeng Fan ◽  
Shufang Liu
Keyword(s):  
Transient Receptor Potential ◽  
Specific Inhibitor ◽  
Receptor Potential ◽  
Nuclear Factor Κb ◽  
Erk Pathway ◽  
Ang Ii ◽  
Extracellular Signal ◽  
Intracellular Ca ◽  
Apoptosis Inducer ◽  
Transient Receptor

Angiotensin II (Ang II) has been recognized as an apoptosis inducer in podocytes, but the mechanism of apoptosis induced by Ang II is unclear. Transient receptor potential cation channel 6 (TRPC6) is a calcium channel located in podocyte membrane. The present study evaluated the alteration of TRPC6 expression and the Ca2+ influx involved in Ang II-induced podocyte apoptosis. The possible pathways related to TRPC6 in Ang II-induced podocyte apoptosis were also investigated. The apoptosis of mouse podocytes (MPC5) was induced by Ang II. The protein level of TRPC6 was increased markedly in response to Ang II stimulation, and the intracellular Ca2+ concentration was elevated. By transfection with TRPC6 siRNA, Ang II-induced podocyte apoptosis and the transient Ca2+ influx were inhibited. Treated with extracellular signal-regulated kinase (ERK) pathway specific inhibitor U0126 or nuclear factor-κB (NF-κB) pathway specific inhibitor ammonium pyrrolidinedithiocarbamate (PDTC) and Ang II, respectively in podocytes, not only was the TRPC6 up-regulation reduced, but the podocyte apoptosis was also decreased. Moreover, the translocation of NF-κB in nucleus resulted from Ang II was reduced by treatment with U0126. In conclusion, the enhancement expression of TRPC6 as well as the increased Ca2+ influx mediated by TRPC6 channels contributed to the podocyte apoptosis. The activation of ERK pathway and subsequent translocation of NF-κB was possibly necessary for the up-regulation TRPC6 induced by Ang II.

Abstract 14287: Ang II-induced Pathological Autophagy is Inhibited by IL-10 via Akt Dependent Inhibition of Beclin 1 in Mice Heart

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Suresh K Verma ◽  
Prasanna Krishnamurthy ◽  
Venkata N Girikipathi ◽  
Tatiana Abramova ◽  
Anna Gumpert ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Chronic Heart Failure ◽  
Cardiac Function ◽  
Beclin 1 ◽  
Neonatal Rat ◽  
Autophagic Flux ◽  
Physical Interaction ◽  
Ang Ii

Although, autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation on autophagic process would be important to treat chronic heart failure. Previously, we have shown that IL-10 strongly improved cardiac function in chronic heart failure models, but the role of IL-10 in regulation of pathological autophagy is not yet investigated. We tested the hypothesis that IL-10 inhibits angiotensin II-induced pathological autophagy and thus improved cardiac function. Pathological autophagy was induced in wild type (WT) and IL10-knockout mice by angiotensin II infusion. Ang II-induced left ventricular dysfunction and hypertrophic remodeling were accentuated in IL-10 KO mice compared to WT mice. IL-10 KO mice showed exaggerated autophagy with reduced AKT phosphorylation. In neonatal rat ventricular cardiomyocytes, Ang II activated beclin1 and LC3 levels and inhibited AKT/mTORC1 and AKT-Bcl2 signaling. IL-10 inhibited Ang II-induced autophagic marker proteins. Additionally, IL-10 restored Ang II effects on AKT/mTORC1 and AKT-Bcl2 signaling. Both pharmacological/molecular inhibition of AKT via PI3K inhibitor (LY290002) or Akt siRNA, attenuated IL-10 effects on the Ang II-induced pathological autophagy, confirming that IL-10 mediated regulation of pathological autophagy is AKT dependent. Similar results were observed with mTORC1 inhibitor rapamycin. Chloroquine (a lysosome inhibitor) strongly inhibits Ang II-induced autophagic flux. However, chloroquine did not affect IL-10 effects on autophagic flux, suggesting that IL-10 inhibits stress-induced pathological autophagy. Finally, as physical interaction of Bcl2 with beclin 1 is important to inhibit autophagy and IL-10 is strong activator of Bcl2, we performed immunoprecipitation experiment. Immunoprecipitation data suggested that Ang II disrupt the physical interaction of beclin 1 with Bcl2 and IL-10 reestablished this physical interaction to reduce autophagy. Our data give a novel role of IL-10 in regulation of pathological autophagy and thus can act as a potential therapeutic molecule in treatment of chronic heart disease.

Abstract 172: Interleukin-10-mediated Activation of AKT and Bcl2 Inhibits Chronic Angiotensin II-induced Pathological Autophagy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Suresh K Verma ◽  
Prasanna Krishnamurthy ◽  
Venkata N Girikipathi ◽  
Tatiana Abramova ◽  
Moshin Khan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Pressure Overload ◽  
Interleukin 10 ◽  
Left Ventricular ◽  
Beclin 1 ◽  
Neonatal Rat ◽  
Physical Interaction ◽  
Ang Ii

Rationale: Although, autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological (stress-induced exaggerated/defective) autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation of autophagic process would be important to treat chronic heart failure. Previously, we have shown that IL-10 strongly inhibited pressure overload-induced hypertrophy and heart failure, but role of IL-10 in regulation of pathological autophagy is not known. Hypothesis: We tested the hypothesis that IL-10 inhibits angiotensin II-induced pathological autophagy and this process, in part, led to improved cardiac function. Methods and Results: Pathological autophagy was induced in wild type (WT) and IL10-knockout (IL-10 KO) mice by angiotensin II (Ang II for 28 days) infusion. Ang II-induced left ventricular (LV) dysfunction and hypertrophic remodeling were accentuated in IL-10 KO mice compared to WT mice. IL-10 KO mice showed exaggerated autophagy as observed by Electron Microscopy and Western blotting (beclin 1, LC3 II/I and CHOP) with reduced AKT phosphorylation at serine-473. In neonatal rat ventricular cardiomyocytes (NRCM), Ang II treatment enhanced beclin1, LC3 and CHOP protein levels and inhibited AKT and 4EBP1 phosphorylation and Bcl2 levels. Interestingly, IL-10 inhibited Ang II-induced autophagic marker proteins. Additionally, IL-10 restored Ang II-induced suppression of AKT and 4EBP1 phosphrylation and restoration of Bcl2 protein level. Pharmacological inhibition of AKT via PI3K inhibitor (LY290002), reversed IL-10 responses on the Ang II-induced pathological autophagy, confirming that IL-10 mediated inhibition of autophagy is AKT dependent. Finally, as physical interaction of Bcl2 with beclin 1 is important to inhibit autophagy, we performed immunoprecipitation pull-down experiments, which showed Ang II disrupts the physical interaction of beclin 1 with Bcl2 and IL-10 reestablished this physical interaction to reduce autophagy. Conclusion: Our data provides a novel role of IL-10 in regulation of pathological autophagy and thus can act as a potential therapeutic molecule in treatment of chronic heart disease.

scholarly journals Myeloid Differentiation Protein 2 Mediates Angiotensin II-Induced Liver Inflammation and Fibrosis in Mice

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 25 ◽  
Author(s):  
Yi Zhang ◽  
Hui Liu ◽  
Wenjing Jia ◽  
Jiayu Qi ◽  
Wentao Zhang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Liver Injury ◽  
Critical Role ◽  
Myeloid Differentiation ◽  
Ang Ii ◽  
Liver Inflammation ◽  
Protein Levels ◽  
Extracellular Signal ◽  
Injury Model

Angiotensin II (Ang II) participates in the pathogenesis of liver injury. Our previous publications reported that myeloid differentiation protein 2 (MD2) mediates Ang II-induced cardiac and kidney inflammation by directly binding to Ang II. Thus, we hypothesize that MD2 is critical to Ang II-induced liver injury. Subcutaneous injections of Ang II for 8 weeks were adopted to build the liver injury model. With a specific MD2 inhibitor L6H21 and MD2 knockout mice, we reported that MD2 inhibition and knockout significantly mitigate liver inflammation and fibrosis in mice injected with Ang II. To be more specific, the functional and pathological damages induced by Ang II were mitigated by L6H21 or MD2 knockout. MD2 knockout or L6H21 administration inhibited the Ang II-induced upregulation of fibrosis markers, inflammatory cytokines, and adhesion molecules in gene or protein levels. The activation of NF-κB and Extracellular signal-regulated kinases (ERK) induced by Ang II was also reversed by L6H21 treatment or MD2 deficiency. Note that the co-immunoprecipitation study showed that L6H21 downregulated the ANG II-induced toll-like receptor 4 (TLR4)/MD2 complex in liver tissues while having no effects on MD2 expression. Our results reported the critical role of MD2 in the progress of liver injury and suggested that MD2 is a potential therapeutic target for liver injury.

The Role of Apoptosis in Myocyte Death During Cardiac Hypertrophy

2001 ◽  
Vol 7 (S2) ◽  
pp. 596-597
Author(s):  
E.C. Goldsmith ◽  
J.G. Davis ◽  
X. Yan ◽  
B.H. ᒫorell ◽  
T.K. Borg ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Development ◽  
Mechanical Stimulus ◽  
Type I ◽  
Integrin Subunit ◽  
Ang Ii ◽  
Adult Rat ◽  
Rat Myocytes

Apoptotic events can be the result of both cell anchorage-dependent and independent mechanisms. The term “anoikis” has been used to describe apoptotic events resulting from a lack of cell-ECM contact (Frisch and Francis, 1994). The integrin heterodimer α5β1 has been implicated in several systems as providing protection against apoptosis. Previous studies have demonstrated that the α5 integrin subunit is present only during cardiac development and conditions of cardiac hypertrophy and is not found in normal adult rat myocytes (Terracio et al., 1991). Cell anchorage-independent apoptosis can result from a variety of factors including biochemical and mechanical stimulus. Angiotensin II (Ang II) has been implicated as a modulator of myocyte apoptosis acting through the angiotensin II type I receptor (Kajstura et al., 1997). The role of a second Ang II receptor, angiotensin II type 2 receptor, has not been determined. The role of apoptosis in myocyte cell death during heart failure remains unclear.

P5395Exercise-induced miR-17-3p Prevents Pathological Myocardial Dysfunction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Q Zhou ◽  
J Xiao
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Cell Area ◽  
Ang Ii ◽  
Upstream Regulator ◽  
Exercise Induced

Abstract Background Exercise is beneficial for pathological myocardial dysfunction and heart failure. We previously reported that miR-17-3p contributed to exercise-induced cardiac growth and protected against cardiac ischemia/reperfusion injury. However, if exercise-induced miR-17-3p can prevent pathological myocardial dysfunction is undetermined. Purpose To investigate if exercise-induced miR-17-3p can prevent pathological myocardial dysfunction. Methods The miR-17-3p expression was examined in phenylephrine (PE, 50μmol/L, 48 h) and angiotensin II (Ang II, 1μmol/L, 48 h) treated primary neonatal rat ventricular cardiomyocytes (NRCM), and the myocardium of thoracic aortic constriction (TAC, 4weeks) or angiotensin II (1.3 mg/kg/day, 4weeks) induced cardiac hypertrophy murine model. miR-17-3p transgenic mice were generated and subjected to TAC or Ang II to investigate the effect of miR-17-3p overexpression in attenuating pathological cardiac dysfunction by echocardiography. Cell area and hypertrophic genes were determined by Wheat Germ Agglutinin (WGA) staining and qRT-PCRs. In addition, cell area and hypertrophic genes (ANP, BNP, β-MHC) were determined by immunolabeling and qRT-PCR in NRCM after the transfection of miR-17-3p mimic or inhibitor. Furthermore, functional rescue assays were performed to identify phosphatase and tensin homolog (PTEN) as a target gene of miR-17-3p, and myocyte enhancer factor 2C (MEF2C) as an upstream regulator of miR-17-3p in pathological cardiac hypertrophy. Results The expression of miR-17-3p was significantly decreased in the heart from TAC or Ang II mouse model, and in PE or Ang II-induced cardiomyocyte hypertrophy model. miR-17-3p overexpression mice displayed improved cardiac function and reduced cardiac hypertrophy after TAC or Ang II treatment in vivo. miR-17-3p mimic significantly attenuated PE or Ang II-induced cardiomyocyte hypertrophy in vitro. Based on functional rescue experiments, PTEN was identified as a direct target of miR-17-3p that mediated its protective effects in cardiac hypertrophy. Moreover, MEF2C was identified as a negative upstream regulator of miR-17-3p involved in the control of cardiac hypertrophy. Proposed mechanism of miR-17-3p Conclusion Exercise-induced miR-17-3p can prevent pathological myocardial dysfunction by targeting PTEN. MEF2C was an upstream regulator of miR-17-3p. Targeting MEF2C/miR-17-3p/ PTEN represents a novel therapeutic strategy for pathological myocardial dysfunction. Acknowledgement/Funding The grants from National Natural Science Foundation of China (81722008, 91639101 and 81570362 to JJ Xiao)

scholarly journals I-κB Kinase-ε Deficiency Attenuates the Development of Angiotensin II-Induced Myocardial Hypertrophy in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Yide Cao ◽  
Liangpeng Li ◽  
Yafeng Liu ◽  
Ganyi Chen ◽  
Zhonghao Tao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Myocardial Hypertrophy ◽  
Peptide Hormone ◽  
Mitogen Activated Protein Kinase ◽  
Mouse Heart ◽  
Ang Ii ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

I-κB kinase-ε (IKKε) is a member of the IKK complex and a proinflammatory regulator that is active in many diseases. Angiotensin II (Ang II) is a vasoconstricting peptide hormone, and Ang II-induced myocardial hypertrophy is a common cardiovascular disease that can result in heart failure. In this study, we sought to determine the role of IKKε in the development of Ang II-induced myocardial hypertrophy in mice. Wild-type (WT) and IKKε-knockout (IKKε-KO) mice were generated and infused with saline or Ang II for 8 weeks. We found that WT mouse hearts have increased IKKε expression after 8 weeks of Ang II infusion. Our results further indicated that IKKε-KO mice have attenuated myocardial hypertrophy and alleviated heart failure compared with WT mice. Additionally, Ang II-induced expression of proinflammatory and collagen factors was much lower in the IKKε-KO mice than in the WT mice. Apoptosis and pyroptosis were also ameliorated in IKKε-KO mice. Mechanistically, IKKε bound to extracellular signal-regulated kinase (ERK) and the mitogen-activated protein kinase p38, resulting in MAPK/ERK kinase (MEK) phosphorylation, and IKKε deficiency inhibited the phosphorylation of MEK-ERK1/2 and p38 in mouse heart tissues after 8 weeks of Ang II infusion. The findings of our study reveal that IKKε plays an important role in the development of Ang II-induced myocardial hypertrophy and may represent a potential therapeutic target for the management of myocardial hypertrophy.

Abstract 1221: Targeted Deletion of ROCK2 in Cardiomyocytes Prevents Angiotensin II-Induced Cardiac Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Ryuji Okamoto ◽  
Kensuke Noma ◽  
Naoki Sawada ◽  
Yukio Hiroi ◽  
Ping-Yen Liu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Systolic Function ◽  
Left Ventricular ◽  
Mitogen Activated Protein Kinase ◽  
Heart Weight ◽  
Ang Ii ◽  
Targeted Deletion

Background - Previous studies have shown that Rho kinase (ROCK) inhibitors prevent the development of cardiac hypertrophy. Because ROCK inhibitors inhibit both ROCK isoforms, ROCK1 and ROCK2, the isoform-specific role of ROCK cannot be elucidated from these studies. Hence, a genetic approach with targeted deletion of ROCK in cardiomyocytes provides the best opportunity towards understanding the role of ROCK isoforms in the development of cardiac hypertrophy. Previous studies showed that ROCK1 KO mice develop cardiac hypertrophy to angiotensin II infusion similar to WT mice, but do not develop cardiac fibrosis. However, the role of ROCK2 in the development of cardiac hypertrophy remains to be determined. Methods and Results - Mice deficient in cardiomyocyte-specific ROCK2 (c-ROCK2 −/− ) were generated by crossing mice with loxP-flanked ROCK2 allele with transgenic mice expressing a Cre protein under the control of the cardiomyocyte-specific alpha-myosin heavy chain promoter. The ROCK2 expression levels in the c-ROCK2 −/− mice heart was decreased to less than 30% compared with wild-type mice (ROCK2 +/+ mice) in the whole heart. Heart rate, blood pressures and cardiac systolic function were normal in c-ROCK2 −/− mice. Ang II (400ng/kg/min) or vehicle was subcutaneously infused into c-ROCK2 −/− and ROCK2 +/+ male mice (each group; n=10) for 28 days. Ang II-induced cardiac hypertrophy assessed by an increase in heart weight, left ventricular mass, myocyte cross-sectional area and cardiac hypertrophy-related genes expressions were attenuated in c-ROCK2 −/− mice compared with ROCK2 +/+ mice. The basal activity of extracellular signal-regulated kinase (ERK) were similar in hearts between two groups but the activation of ERK was attenuated and the activity was downregulated earlier in c-ROCK2 −/− than in ROCK2 +/+ mice. The activity of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK) and Akt activity were similar between two groups. Conclusions - These results indicate that ROCK2 is necessary for Ang II-induced cardiac hypertrophy. The mechanism, in part, involves the activation of ERK by ROCK2. Thus, selective ROCK2 inhibitors may be beneficial for preventing cardiac hypertrophy.

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