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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

Mechanical stretch activates mTORC1 in HL-1 cells. Protein contents of the phosphorylated forms of Akt (Ser473 and Thr308), K and S6 in HL-1 cells mechanically stretched for the indicated time. Cells were serum-starved for 4 h then incubated in DMEM supplemented with 0.1 % bovine fetal serum during cyclic stretch. n = 6. Means not sharing a common superscript are significantly different from each other, P < 0.05. Representative blots below graphs
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Fig5: Mechanical stretch activates mTORC1 in HL-1 cells. Protein contents of the phosphorylated forms of Akt (Ser473 and Thr308), K and S6 in HL-1 cells mechanically stretched for the indicated time. Cells were serum-starved for 4 h then incubated in DMEM supplemented with 0.1 % bovine fetal serum during cyclic stretch. n = 6. Means not sharing a common superscript are significantly different from each other, P < 0.05. Representative blots below graphs

Mentions: Severe AR results in important diastolic wall stress and cardiac myocytes stretch. In order to reproduce this type of mechanical stress in vitro, HL-1 cells were submitted to cyclic mechanical stretching before incubation with insulin for 30 min. The phosphorylation levels of various mTOR-related proteins were then measured by immunoblotting (Fig. 5). When a mechanical stretch stress was applied to the cells, S6 kinase and S6 phosphorylation levels increased after 10 and 120 min, respectively. Akt phosphorylation levels on Thr308 remained unchanged while those of S473 were reduced.Fig. 5


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)

Mechanical stretch activates mTORC1 in HL-1 cells. Protein contents of the phosphorylated forms of Akt (Ser473 and Thr308), K and S6 in HL-1 cells mechanically stretched for the indicated time. Cells were serum-starved for 4 h then incubated in DMEM supplemented with 0.1 % bovine fetal serum during cyclic stretch. n = 6. Means not sharing a common superscript are significantly different from each other, P < 0.05. Representative blots below graphs
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: Mechanical stretch activates mTORC1 in HL-1 cells. Protein contents of the phosphorylated forms of Akt (Ser473 and Thr308), K and S6 in HL-1 cells mechanically stretched for the indicated time. Cells were serum-starved for 4 h then incubated in DMEM supplemented with 0.1 % bovine fetal serum during cyclic stretch. n = 6. Means not sharing a common superscript are significantly different from each other, P < 0.05. Representative blots below graphs
Mentions: Severe AR results in important diastolic wall stress and cardiac myocytes stretch. In order to reproduce this type of mechanical stress in vitro, HL-1 cells were submitted to cyclic mechanical stretching before incubation with insulin for 30 min. The phosphorylation levels of various mTOR-related proteins were then measured by immunoblotting (Fig. 5). When a mechanical stretch stress was applied to the cells, S6 kinase and S6 phosphorylation levels increased after 10 and 120 min, respectively. Akt phosphorylation levels on Thr308 remained unchanged while those of S473 were reduced.Fig. 5

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