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Blockade of the acute activation of mTOR complex 1 decreases hypertrophy development in rats with severe aortic valve regurgitation.

Drolet MC, Desbiens-Brassard V, Roussel E, Tu V, Couet J, Arsenault M - Springerplus (2015)

Bottom Line: The role of mTOR inhibition in the development of LVH using rapamycin for relatively short periods of time (days to a few weeks) has been studied in the past in pressure overload models but not in VO models.We observed that a moderate dose of rapamycin (2 mg/kg/day; orally) for 8 weeks prevented severe LVH caused by AR (-46 %: p < 0.001).Rapamycin treatment specifically inhibited LV mTORC1 without altering mTORC2 activity at 8 weeks.

View Article: PubMed Central - PubMed

Affiliation: Groupe de Recherche sur les Valvulopathies, Centre de Recherche de l'Institut universitaire de Cardiologie et pneumologie de Québec, Université Laval, 2725, Chemin Sainte-Foy, Quebec, QC G1V 4G5 Canada.

ABSTRACT

Background: Hypertrophy (H) is an adaptive response of the heart to a hemodynamic overload. Severe left ventricular (LV) volume overload (VO) from valve regurgitations (aortic (AR) or mitral regurgitation) leads to eccentric LVH. Increased protein turnover is a major event during development of LVH and the mechanistic target of rapamycin (mTOR) is a key molecule for its control. The role of mTOR inhibition in the development of LVH using rapamycin for relatively short periods of time (days to a few weeks) has been studied in the past in pressure overload models but not in VO models. We investigated if mTOR pathway was activated during LVH development in a model of severe VO (AR) in rats and if a rapamycin treatment can slow heart remodeling in this situation.

Methods and results: Male rats with severe AR were studied acutely at 2 days, at 8 weeks (compensated phase) and 6 months (late phase) after VO induction. mTOR complex (mTORC) 1 (ribosomal S6 protein phosphorylation) was activated early after AR induction but not later in the disease whereas mTORC2 activity levels (Akt phosphorylation at Ser473) remained stable. We observed that a moderate dose of rapamycin (2 mg/kg/day; orally) for 8 weeks prevented severe LVH caused by AR (-46 %: p < 0.001). Rapamycin treatment specifically inhibited LV mTORC1 without altering mTORC2 activity at 8 weeks. Rapamycin also prevented cardiac myocyte hypertrophy caused by AR.

Conclusion: Rapamycin slows hypertrophy in LV VO by inhibiting early activation of mTORC1 without modulating mTORC2.

No MeSH data available.


Related in: MedlinePlus

Rapamycin inhibits mTORC1 but not mTORC2 LV activity in AR rats. LV protein content of total and phosphorylated forms of Akt, S6 kinase (S6K), S6 and 4EBP-1 in sham and AR rats treated or not with rapamycin. a, b Immunoblotting. c Gene expression of mTOR, S6 Kinase and Akt1 and Akt2. n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05
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Fig2: Rapamycin inhibits mTORC1 but not mTORC2 LV activity in AR rats. LV protein content of total and phosphorylated forms of Akt, S6 kinase (S6K), S6 and 4EBP-1 in sham and AR rats treated or not with rapamycin. a, b Immunoblotting. c Gene expression of mTOR, S6 Kinase and Akt1 and Akt2. n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05

Mentions: Chronic rapamycin treatment has been shown to inhibit not only the activity of the mTORC1 but also of mTORC2 by binding free mTOR and blocking complex formation (Sarbassov et al. 2006). We measured the protein content of four proteins implicated in mTOR signaling namely p70S6 kinase (S6 K), S6, 4EBP1 and Akt. AR did not lead to increased phosphorylation levels of those signaling proteins compared to sham animals at 8 weeks (Fig. 2a, b). On the other hand, rapamycin treatment decreased the protein content ratio of phospho (p)-S6K/S6K, pS6/S6 and p4EBP1/4EBP1 while pAKT (S473)/AKT levels remained stable. We observed in AR and AR + Rapa groups slightly lower levels of the total forms of these signaling molecules suggesting that LV VO could affect their expression. We thus evaluated mTOR, S6K and Akt1 and Akt2 gene expression in the LV of the experimental groups. As illustrated in Fig. 2c, mRNA levels for these four genes remained stable in all groups.Fig. 2


Blockade of the acute activation of mTOR complex 1 decreases hypertrophy development in rats with severe aortic valve regurgitation.

Drolet MC, Desbiens-Brassard V, Roussel E, Tu V, Couet J, Arsenault M - Springerplus (2015)

Rapamycin inhibits mTORC1 but not mTORC2 LV activity in AR rats. LV protein content of total and phosphorylated forms of Akt, S6 kinase (S6K), S6 and 4EBP-1 in sham and AR rats treated or not with rapamycin. a, b Immunoblotting. c Gene expression of mTOR, S6 Kinase and Akt1 and Akt2. n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4542859&req=5

Fig2: Rapamycin inhibits mTORC1 but not mTORC2 LV activity in AR rats. LV protein content of total and phosphorylated forms of Akt, S6 kinase (S6K), S6 and 4EBP-1 in sham and AR rats treated or not with rapamycin. a, b Immunoblotting. c Gene expression of mTOR, S6 Kinase and Akt1 and Akt2. n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05
Mentions: Chronic rapamycin treatment has been shown to inhibit not only the activity of the mTORC1 but also of mTORC2 by binding free mTOR and blocking complex formation (Sarbassov et al. 2006). We measured the protein content of four proteins implicated in mTOR signaling namely p70S6 kinase (S6 K), S6, 4EBP1 and Akt. AR did not lead to increased phosphorylation levels of those signaling proteins compared to sham animals at 8 weeks (Fig. 2a, b). On the other hand, rapamycin treatment decreased the protein content ratio of phospho (p)-S6K/S6K, pS6/S6 and p4EBP1/4EBP1 while pAKT (S473)/AKT levels remained stable. We observed in AR and AR + Rapa groups slightly lower levels of the total forms of these signaling molecules suggesting that LV VO could affect their expression. We thus evaluated mTOR, S6K and Akt1 and Akt2 gene expression in the LV of the experimental groups. As illustrated in Fig. 2c, mRNA levels for these four genes remained stable in all groups.Fig. 2

Bottom Line: The role of mTOR inhibition in the development of LVH using rapamycin for relatively short periods of time (days to a few weeks) has been studied in the past in pressure overload models but not in VO models.We observed that a moderate dose of rapamycin (2 mg/kg/day; orally) for 8 weeks prevented severe LVH caused by AR (-46 %: p < 0.001).Rapamycin treatment specifically inhibited LV mTORC1 without altering mTORC2 activity at 8 weeks.

View Article: PubMed Central - PubMed

Affiliation: Groupe de Recherche sur les Valvulopathies, Centre de Recherche de l'Institut universitaire de Cardiologie et pneumologie de Québec, Université Laval, 2725, Chemin Sainte-Foy, Quebec, QC G1V 4G5 Canada.

ABSTRACT

Background: Hypertrophy (H) is an adaptive response of the heart to a hemodynamic overload. Severe left ventricular (LV) volume overload (VO) from valve regurgitations (aortic (AR) or mitral regurgitation) leads to eccentric LVH. Increased protein turnover is a major event during development of LVH and the mechanistic target of rapamycin (mTOR) is a key molecule for its control. The role of mTOR inhibition in the development of LVH using rapamycin for relatively short periods of time (days to a few weeks) has been studied in the past in pressure overload models but not in VO models. We investigated if mTOR pathway was activated during LVH development in a model of severe VO (AR) in rats and if a rapamycin treatment can slow heart remodeling in this situation.

Methods and results: Male rats with severe AR were studied acutely at 2 days, at 8 weeks (compensated phase) and 6 months (late phase) after VO induction. mTOR complex (mTORC) 1 (ribosomal S6 protein phosphorylation) was activated early after AR induction but not later in the disease whereas mTORC2 activity levels (Akt phosphorylation at Ser473) remained stable. We observed that a moderate dose of rapamycin (2 mg/kg/day; orally) for 8 weeks prevented severe LVH caused by AR (-46 %: p < 0.001). Rapamycin treatment specifically inhibited LV mTORC1 without altering mTORC2 activity at 8 weeks. Rapamycin also prevented cardiac myocyte hypertrophy caused by AR.

Conclusion: Rapamycin slows hypertrophy in LV VO by inhibiting early activation of mTORC1 without modulating mTORC2.

No MeSH data available.


Related in: MedlinePlus