Src Is Required for Mechanical Stretch-Induced Cardiomyocyte Hypertrophy through Angiotensin II Type 1 Receptor-Dependent β-Arrestin2 Pathways

Background/Aims: Angiotensin II (AngII) type 1 receptor (AT1R) could be activated by mechanical stress without the involvement of AngII during the development of cardiac hypertrophy. We aimed to identify sensing sites of AT1R for activation by mechanical stretch. Methods: We constructed several site-directed mutations of AT1R (AT1RK199Q, AT1RL212F, AT1RQ257A and AT1RC289A), transfected them respectively into COS7 cells or angiotensinogen knockout cardiomyocytes (ATG−/−-CMs), and observed cellular events after mechanical stretch. Results: AngII-induced phosphorylation of ERKs and Jak2, and redistribution of Gαq11 in AT1RWT- COS7 or -ATG−/−-CMs were dramatically decreased in AT1RK199Q- or AT1RQ257A- COS7 cells or -ATG−/−-CMs, while those effects induced by mechanical stretch were greatly suppressed in COS7 cells or ATG−/−-CMs expressing AT1RL212F, AT1RQ257A or AT1RC289A compared with these cells expressing AT1RWT. AngII-induced hypertrophic responses (the increase in hypertrophic genes expression and cross-sectional area) in AT1RWT- ATG−/−-CMs were partly abolished in AT1RK199Q-ATG−/−-CMs or AT1RQ257A-ATG−/−-CMs, while these responses induced by mechanical stretch were greatly inhibited in ATG−/−-CMs overexpressing AT1RL212F, AT1RQ257A or AT1RC289A. Conclusion: These results indicated that Leu212, Gln257 and Cys289 in AT1R are not only sensing sites for mechanical stretch but also functional amino residues for activation of the receptor and cardiomyocytes hypertrophy induced by mechanical stretch.

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The novel angiotensin II type 1 receptor (AT1R)-associated protein ATRAP downregulates AT1R and ameliorates cardiomyocyte hypertrophy

FEBS Letters ◽

10.1016/j.febslet.2005.01.068 ◽

2005 ◽

Vol 579 (7) ◽

pp. 1579-1586 ◽

Cited By ~ 65

Author(s):

Yutaka Tanaka ◽

Kouichi Tamura ◽

Yuichi Koide ◽

Masashi Sakai ◽

Yuko Tsurumi ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiomyocyte Hypertrophy ◽

The Novel

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Abstract 266: Novel Sites of Angiotension II Type 1 Receptor are Identified for Direct Activation by Mechanical Stretch Independent of Angiotension II

Circulation Research ◽

10.1161/res.115.suppl_1.266 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Hui Gong ◽

Guoliang Jiang ◽

Chunjie Yang ◽

Shijun Wang ◽

Zhidan Chen ◽

...

Keyword(s):

Mechanical Stress ◽

Pressure Overload ◽

Mechanical Stretch ◽

Site Directed Mutagenesis ◽

Cardiomyocyte Hypertrophy ◽

Ang Ii ◽

Hypertrophic Response ◽

Angiotension Ii ◽

High Level

The angiotensin II type 1 receptor (AT1R) has a crucial role in cardiac hypertrophy induced by pressure overload. In the previous study, we found a novel mechanism for mechanical stress-induced AT1R activation without the involvement of Ang II. However, few reports focus on how AT1R senses mechanical stress and translates it into biochemical signals inside the cells to induce cardiomyocyte hypertrophy. Here, we constructed different site-directed mutagenesis of AT1R and transfected them to COS7 cells and ATG–/– (Angiotensinogen knockout) cardiomyocytes, respectively, to observe the activation of downstream signaling to identify functional site of AT1R. The results showed AT1R-WT, AT1R-K199Q, AT1R-L212F,AT1R-Q257A and AT1R-C289A plasmids or adenovirus were overexpressed at high level in plasma membrane of COS7 or cardiomyocytes respectively. There was no obvious difference in subcellular expression of wt-AT1R and all the mut-AT1Rs. The further study revealed that Ang II-induced-phosphorylation of ERK, Jak2 and the redistribution of Gαq11 were dramatically decreased in COS7 cells expressing AT1R-K199Q or AT1R-Q257A, while these effects induced by mechanical stretch were greatly suppressed in COS7 cells expressing AT1R-L212F,AT1R-Q257A or AT1R-C289A compared to these in COS7 cells expressing AT1R-WT. We then transfected the adenovirus of wt-AT1R or different mut-AT1Rs to ATG–/– cardiomyocytes to exclude the influence of endogenous Ang II. The results were consistent with these results in COS7 cells. Moreover, ATG–/– cardiomyocytes overexpressing AT1R-K199Q or AT1R-Q257A parlty abolished hypertrophic response induce by Ang II, while the cardiomyocytes overexpressing AT1R-L212F,AT1R-Q257A or AT1R-C289A greatly inhibited the hypertrophic response induced by mechanical stretch. The present study indicated that Leu212, Gln257 and Cys289 are critical sites for AT1R activation by mechanical stretch without Ang II but Lys199 and Gln257 play important role in AT1R activation with Ang II.

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Angiotensin-II type 1 receptor and NOX2 mediate TCF/LEF and CREB dependent WISP1 induction and cardiomyocyte hypertrophy

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2011.02.012 ◽

2011 ◽

Vol 50 (6) ◽

pp. 928-938 ◽

Cited By ~ 47

Author(s):

Prakashsrinivasan Shanmugam ◽

Anthony J. Valente ◽

Sumanth D. Prabhu ◽

Balachandar Venkatesan ◽

Tadashi Yoshida ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiomyocyte Hypertrophy

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High-Salt Intake Induces Cardiomyocyte Hypertrophy in Rats in Response to Local Angiotensin II Type 1 Receptor Activation

Journal of Nutrition ◽

10.3945/jn.114.192054 ◽

2014 ◽

Vol 144 (10) ◽

pp. 1571-1578 ◽

Cited By ~ 17

Author(s):

Isis A. Katayama ◽

Rafael C. Pereira ◽

Ellen P. B. Dopona ◽

Maria H. M. Shimizu ◽

Luzia N. S. Furukawa ◽

...

Keyword(s):

Angiotensin Ii ◽

Salt Intake ◽

Receptor Activation ◽

High Salt ◽

Cardiomyocyte Hypertrophy ◽

High Salt Intake

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Mechanical Stretch Stimulates Protein Kinase B/Akt Phosphorylation in Epidermal Cells via Angiotensin II Type 1 Receptor and Epidermal Growth Factor Receptor

Journal of Biological Chemistry ◽

10.1074/jbc.m409590200 ◽

2004 ◽

Vol 280 (4) ◽

pp. 3060-3067 ◽

Cited By ~ 71

Author(s):

Stefan Kippenberger ◽

Stefan Loitsch ◽

Maike Guschel ◽

Jutta Müller ◽

Yvonne Knies ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Angiotensin Ii ◽

Growth Factor ◽

Protein Kinase ◽

Protein Kinase B ◽

Growth Factor Receptor ◽

Mechanical Stretch ◽

Akt Phosphorylation ◽

Epidermal Growth

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Thyroid Hormone Increases TGF-β1 in Cardiomyocytes Cultures Independently of Angiotensin II Type 1 and Type 2 Receptors

International Journal of Endocrinology ◽

10.1155/2010/384890 ◽

2010 ◽

Vol 2010 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Gabriela Placoná Diniz ◽

Marcela Sorelli Carneiro-Ramos ◽

Maria Luiza Morais Barreto-Chaves

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Angiotensin Ii Receptors ◽

Cardiomyocyte Hypertrophy ◽

Tgf Β1

TH-induced cardiac hypertrophyin vivois accompanied by increased cardiac Transforming Growth Factor-β1 (TGF-β1) levels, which is mediated by Angiotensin II type 1 receptors (AT1R) and type 2 receptors (AT2R). However, the possible involvement of this factor in TH-induced cardiac hypertrophy is unknown. In this study we evaluated whether TH is able to modulate TGF-β1 in isolated cardiac, as well as the possible contribution of AT1R and AT2R in this response. The cardiac fibroblasts treated withT3did not show alteration on TGF-β1 expression. However, cardiomyocytes treated withT3presented an increase in TGF-β1 expression, as well as an increase in protein synthesis. The AT1R blockade prevented theT3-induced cardiomyocyte hypertrophy, while the AT2R blockage attenuated this response. TheT3-induced increase on TGF-β1 expression in cardiomyocytes was not changed by the use of AT1R and AT2R blockers. These results indicate that Angiotensin II receptors are not implicated inT3-induced increase on TGF-βexpression and suggest that the trophic effects exerted byT3on cardiomyocytes are not dependent on the higher TGF-β1 levels, since the AT1R and AT2R blockers were able to attenuate theT3-induced cardiomyocyte hypertrophy but were not able to attenuate the increase on TGF-β1 levels promoted byT3.

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