Differential Activation of p70 and p85 S6 Kinase Isoforms during Cardiac Hypertrophy in the Adult Mammal

Cardiovascular diseases are the leading cause of death worldwide. One in three cases of heart failure is due to dilated cardiomyopathy. The Na+/H+ exchanger isoform 1 (NHE1), a multifunctional protein and the key pH regulator in the heart, has been demonstrated to be increased in this condition. We have previously demonstrated that elevated NHE1 activity induced cardiac hypertrophy in vivo. Furthermore, the overexpression of active NHE1 elicited modulation of gene expression in cardiomyocytes including an upregulation of myocardial osteopontin (OPN) expression. To determine the role of OPN in inducing NHE1-mediated cardiomyocyte hypertrophy, double transgenic mice expressing active NHE1 and OPN knockout were generated and assessed by echocardiography and the cardiac phenotype. Our studies showed that hearts expressing active NHE1 exhibited cardiac remodeling indicated by increased systolic and diastolic left ventricular internal diameter and increased ventricular volume. Moreover, these hearts demonstrated impaired function with decreased fractional shortening and ejection fraction. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA was upregulated, and there was an increase in heart cell cross-sectional area confirming the cardiac hypertrophic effect. Moreover, NHE1 transgenic mice also showed increased collagen deposition, upregulation of CD44 and phosphorylation of p90 ribosomal s6 kinase (RSK), effects that were regressed in OPN knockout mice. In conclusion, we developed an interesting comparative model of active NHE1 transgenic mouse lines which express a dilated hypertrophic phenotype expressing CD44 and phosphorylated RSK, effects which were regressed in absence of OPN.

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Differential Activation of Mitogen-activated Protein Kinase and S6 Kinase Signaling Pathways by 12-O-Tetradecanoylphorbol-13-acetate (TPA) and Insulin

Journal of Biological Chemistry ◽

10.1074/jbc.270.47.28325 ◽

1995 ◽

Vol 270 (47) ◽

pp. 28325-28330 ◽

Cited By ~ 39

Author(s):

Rony Seger ◽

Yael Biener ◽

Revital Feinstein ◽

Tamar Hanoch ◽

Aviv Gazit ◽

...

Keyword(s):

Protein Kinase ◽

Signaling Pathways ◽

Mitogen Activated Protein Kinase ◽

Kinase Signaling ◽

S6 Kinase ◽

Differential Activation ◽

Mitogen Activated Protein

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Abstract 190: Disruption of P90 Ribosomal S6 Kinase Binding 3 to Muscle A-kinase Anchoring Protein In Vivo Via Adeno-associated Virus Expression of a Competing Peptide Attenuates Pressure Overload-induced Cardiac Hypertrophy

Circulation Research ◽

10.1161/res.115.suppl_1.190 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

CATHERINE L PASSARIELLO ◽

Michael D Kritzer ◽

Hrishikesh Thakur ◽

Michael Sanders ◽

Jinliang Li ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Myocyte ◽

Troponin T ◽

Pressure Overload ◽

Compensatory Response ◽

S6 Kinase ◽

Anchoring Protein ◽

P90 Ribosomal S6 Kinase ◽

Ribosomal S6 Kinase

RATIONALE: Cardiac myocyte hypertrophy is the main compensatory response to chronic stress in the heart. p90 ribosomal S6 kinase (RSK) family members are effectors for extracellular signal-regulated kinases that induce myocyte growth. RSK3 contains a unique N-terminal domain that mediates RSK3 binding to the muscle A-kinase anchoring protein (mAKAPβ) scaffold. We have previously published that disruption of RSK3-mAKAPβ complexes using a competing peptide inhibited the phenylephrine-induced hypertrophy of neonatal ventricular myocytes in vitro. In vivo, RSK3 gene deletion in mice attenuated the concentric cardiac hypertrophy induced by pressure overload. We hypothesize that RSK3 anchoring to mAKAPβ in myocytes is required for cardiac hypertrophy in vivo. METHODS AND RESULTS: Adeno-associated viruses (AAV) are gene therapy vectors in development for the treatment of human diseases owing to their nonpathogenic capability for transducing non-dividing cells and their long-term transgene expression. We have used a recombinant AAV2/9 vector to express a mAKAPβ RSK3-binding domain (RBD)-GFP fusion protein under the control of the cardiac myocyte-specific cardiac troponin T promoter. 3 day-old C57BL/6 mice were injected intraperitoneally with either AAV-RBD-GFP or AAV-GFP control virus. At 8 weeks of age mice were subjected to transverse aortic constriction to induce pressure overload (TAC) for two weeks. Cardiac hypertrophy was attenuated in mice injected with the AAV-RBD-GFP virus (biventricular weight indexed to tibial length (mg/mm): 7.7, 8.6, and 9.2 for AAV-RBD, AAV-GFP and non-injected TAC cohorts, respectively; p<0.05 vs. both controls). Echocardiography both corroborated the inhibition of hypertrophy and revealed no deleterious effect on cardiac function attributable to the AAV-RBD-GFP vector. CONCLUSIONS: Anchored RSK3 regulates pathologic myocyte growth. AAV can successfully deliver a competing peptide inhibiting pathological hypertrophy and should be investigated further as a prevention and/or treatment for heart failure.

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Activation of cardiac ERK, Akt and S6 kinase, but not PKC, prior to cardiac hypertrophy in spontaneously hypertensive rats

The FASEB Journal ◽

10.1096/fasebj.20.4.a638 ◽

2006 ◽

Vol 20 (4) ◽

Author(s):

Thunder Jalili ◽

Shane Lefler ◽

J. David Symons ◽

Justin Carlstrom

Keyword(s):

Cardiac Hypertrophy ◽

Spontaneously Hypertensive Rats ◽

Hypertensive Rats ◽

S6 Kinase ◽

Spontaneously Hypertensive

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Rapamycin Prevents Thyroid Hormone-Induced Cardiac Hypertrophy

Endocrinology ◽

10.1210/en.2007-0099 ◽

2007 ◽

Vol 148 (7) ◽

pp. 3477-3484 ◽

Cited By ~ 84

Author(s):

James A. Kuzman ◽

Timothy D. O’Connell ◽

A. Martin Gerdes

Keyword(s):

Protein Synthesis ◽

Cardiac Hypertrophy ◽

Mammalian Target Of Rapamycin ◽

Kinase Signaling ◽

Akt Signaling Pathway ◽

S6 Kinase ◽

Neonatal Cardiomyocytes ◽

Neonatal Cardiomyocyte

Thyroid hormones (THs) have many effects on the cardiovascular system including cardiac hypertrophy. Although THs induce cardiac hypertrophy, the mechanism through which they exert this effect is unknown. We previously found that THs activate signaling related to increased protein synthesis [mammalian target of rapamycin (mTOR) and p70 S6 kinase] in the heart. It is unknown whether this activation contributes to TH-induced hypertrophy or whether it is merely incidental. In this study, we used rapamycin to inhibit mTOR function in mice and neonatal cardiomyocyte cultures treated with THs to test whether mTOR/S6 kinase signaling is involved in TH-mediated cardiac hypertrophy. C57 mice were treated with T4 for 3 d, 1 wk, 2 wk, or 1 month with either placebo, T4 (50 μg/100 g body weight·d), rapamycin (200 μg/100 g body weight·d) or T4/rapamycin by sc slow-release pellets. At the end of the treatment period, hemodynamics and physical data were collected and hearts were frozen for Western blot analysis or myocytes were isolated. The effects of T3 and rapamycin were also investigated using neonatal cardiomyocytes. THs activated specific components of the AKT signaling pathway in vivo and in vitro. THs induced cardiac hypertrophy, which was completely inhibited by rapamycin. Our results suggest that TH-induced hypertrophy is mediated by AKT/mTOR/S6 kinase signaling, which is important in the regulation of protein synthesis, a hallmark of cardiac hypertrophy.

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