Activation of p70 S6 protein kinase is necessary for angiotensin II‐induced hypertrophy in neonatal rat cardiac myocytes

Takano, Hiroyuki; Komuro, Issei; Zuu, Yunzeng; Kudoh, Sumiyo; Yamazaki, Tsutomu; Yazaki, Yoshio

doi:10.1016/0014-5793(95)01523-x

Cited by 45 publications

(22 citation statements)

References 36 publications

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“…Previous studies have provided strong evidence that p70 S6 protein kinase plays an important role in Ang II-induced protein synthesis and vascular hypertrophy. 21,22 Mammalian TOR (target of rapamycin) regulates cell growth predominantly via activation of the p70 S6 kinase. 58 The novel immunosuppressant everolimus is a proliferation signal inhibitor that blocks growth factordriven proliferation of T cells, B cells, and VSMC by inhibiting activation of p70 S6 kinase.…”

Section: Discussionmentioning

confidence: 99%

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Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Finckenberg

Inkinen

Ahonen

et al. 2003

The American Journal of Pathology

102

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Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis.Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collagen degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang II in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang II induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. CTGF overexpression correlated closely with the Ang II-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGF␤ 1 , collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang II-induced cell proliferation and apoptosis. In contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cellmediated inflammation. Our findings provide evidence that CTGF mediates Ang II-induced fibrosis in the heart and kidneys via blood pressure and cal-

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Section: Discussionmentioning

confidence: 99%

“…We then examined whether or not calcineurin-dependent pathways participate in regulating CTGF gene expression. Since Ang II-induced protein synthesis and vascular hypertrophy are strongly dependent on p70 S6 kinase activation, 21,22 we also studied the effects of p70 S6 inhibition by SDZ RAD (everolimus).…”

mentioning

confidence: 99%

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Finckenberg

Inkinen

Ahonen

et al. 2003

The American Journal of Pathology

102

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“…mTORC1 lies upstream of critical translation regulators such as the 40S ribosomal protein S6 kinase 1 (S6K1; also known as RPS6KB1) and the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1; Proud 2004). Activation of the mTORC1 pathway is a critical step to induce cardiac hypertrophy in vitro (Takano et al 1996, Boluyt et al 1997, Simm et al 1998, Rolfe et al 2005, Kenessey & Ojamaa 2006 and in vivo (Shioi et al 2003, McMullen et al 2004, Gao et al 2006, Kuzman et al 2007, Kemi et al 2008. Pro-hypertrophic stimuli can regulate mTORC1 signaling, mainly activating either the phosphatidylinositol 3-kinase (PI3K)/Akt (Shioi et al 2002, Kenessey & Ojamaa 2006 or the MEK/extracellular signal-regulated kinase 1/2 (ERK1/2) pathways (Wang & Proud 2002, Rolfe et al 2005.…”

Section: Introductionmentioning

confidence: 99%

Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway

Altamirano¹,

Oyarce²,

Silva³

et al. 2009

Journal of Endocrinology

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Elevated testosterone concentrations induce cardiac hypertrophy but the molecular mechanisms are poorly understood. Anabolic properties of testosterone involve an increase in protein synthesis. The mammalian target of rapamycin complex 1 (mTORC1) pathway is a major regulator of cell growth, but the relationship between testosterone action and mTORC1 in cardiac cells remains unknown. Here, we investigated whether the hypertrophic effects of testosterone are mediated by mTORC1 signaling in cultured cardiomyocytes. Testosterone increases the phosphorylation of mTOR and its downstream targets 40S ribosomal protein S6 kinase 1 (S6K1; also known as RPS6KB1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The S6K1 phosphorylation induced by testosterone was blocked by rapamycin and small interfering RNA to mTOR. Moreover, the hormone increased both extracellular-regulated kinase (ERK1/2) and protein kinase B (Akt) phosphorylation. ERK1/2 inhibitor PD98059 blocked the testosterone-induced S6K1 phosphorylation, whereas Akt inhibition (Akt-inhibitor-X) had no effect. Testosterone-induced ERK1/2 and S6K1 phosphorylation increases were blocked by either 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid-acetoxymethylester or by inhibitors of inositol 1,4,5-trisphosphate (IP 3 ) pathway: U-73122 and 2-aminoethyl diphenylborate. Finally, cardiomyocyte hypertrophy was evaluated by, the expression of b-myosin heavy chain, a-skeletal actin, cell size, and amino acid incorporation. Testosterone increased all four parameters and the increase being blocked by mTOR inhibition. Our findings suggest that testosterone activates the mTORC1/S6K1 axis through IP 3 /Ca 2C and MEK/ERK1/2 to induce cardiomyocyte hypertrophy.

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“…Once activated, mTOR phosphorylates p70 S6K , a mitogen-and amino acid sensitive kinase which is involved in regulating the translation of elongation factor and ribosomal mRNAs (31). In skeletal, cardiac and smooth muscle, p70 S6K phosphorylation has been shown to be induced by a variety of hypertrophic agonists such as angiotensin II, α-or β-adrenergic receptor agonists and increased mechanical load (32)(33)(34)(35). Our data imply that fluprostenol may also be included in this list.…”

Section: Discussionmentioning

confidence: 74%

PGF2α-associated vascular smooth muscle hypertrophy is ROS dependent and involves the activation of mTOR, p70S6k, and PTEN

Rice

Uddemarri

Desai

et al. 2008

Prostaglandins & Other Lipid Mediators

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Prostaglandin F 2α (PGF2α) increases reactive oxygen species (ROS) and induces vascular smooth muscle cell (VSMC) hypertrophy by largely unknown mechanism(s). To investigate the signaling events governing PGF2α -induced VSMC hypertrophy we examined the ability of the PGF2α analog, fluprostenol to elicit phosphorylation of Akt, the mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70 S6k ), glycogen synthase kinase-3β (GSK-3β), phosphatase and tensin homolog (PTEN), extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) in growth arrested A7r5 VSMC. Fluprostenol-induced hypertrophy was associated with increased ROS, mTOR translocation from the nucleus to the cytoplasm, along with Akt, mTOR, GSK-3β, PTEN and ERK1/2 but not JNK phosphorylation. Whereas inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002 blocked fluprostenol-induced changes in total protein content, pretreatment with rapamycin or with the ERK1/2-MAPK inhibitor UO126 did not. Taken together, these findings suggest that fluprostenol-induced changes in A7R5 hypertrophy involve mTOR translocation and occur through PI3K-dependent mechanisms.

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Activation of p70 S6 protein kinase is necessary for angiotensin II‐induced hypertrophy in neonatal rat cardiac myocytes

Cited by 45 publications

References 36 publications

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway

PGF2α-associated vascular smooth muscle hypertrophy is ROS dependent and involves the activation of mTOR, p70S6k, and PTEN

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