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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

Focal adhesion kinase (FAK) activation in LV VO. Protein contents of the phosphorylated and total forms of FAK (Y397) were evaluated by immunoblotting in the left ventricles of AR rats two days (a) and 8 weeks (b) post-surgery. n = 8. Means not sharing a common superscript are significantly different from each other, P < 0.05. Representative blots below graphs. The 8-week pFAK blot is presented in two different panels as a molecular weight marker was cropped from the image between Sham and AR samples
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Fig6: Focal adhesion kinase (FAK) activation in LV VO. Protein contents of the phosphorylated and total forms of FAK (Y397) were evaluated by immunoblotting in the left ventricles of AR rats two days (a) and 8 weeks (b) post-surgery. n = 8. Means not sharing a common superscript are significantly different from each other, P < 0.05. Representative blots below graphs. The 8-week pFAK blot is presented in two different panels as a molecular weight marker was cropped from the image between Sham and AR samples

Mentions: Focal adhesion kinase (FAK) is implicated in the signal transduction of mechanical stress. Two days post-AR, both FAK and pFAK were increased in the LV (Fig. 6a) while it was not the case later at 8 weeks (Fig. 6b). Rapamycin treatment decreased FAK phosphorylation in both sham-operated and AR animals. We also measured the pFAK(Y397)/FAK ratio in stretched HL-1 cells. We observed a strong trend for an increase of FAK phosphorylation (+70 %; p = 0.055) (not shown).Fig. 6


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)

Focal adhesion kinase (FAK) activation in LV VO. Protein contents of the phosphorylated and total forms of FAK (Y397) were evaluated by immunoblotting in the left ventricles of AR rats two days (a) and 8 weeks (b) post-surgery. n = 8. Means not sharing a common superscript are significantly different from each other, P < 0.05. Representative blots below graphs. The 8-week pFAK blot is presented in two different panels as a molecular weight marker was cropped from the image between Sham and AR samples
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig6: Focal adhesion kinase (FAK) activation in LV VO. Protein contents of the phosphorylated and total forms of FAK (Y397) were evaluated by immunoblotting in the left ventricles of AR rats two days (a) and 8 weeks (b) post-surgery. n = 8. Means not sharing a common superscript are significantly different from each other, P < 0.05. Representative blots below graphs. The 8-week pFAK blot is presented in two different panels as a molecular weight marker was cropped from the image between Sham and AR samples
Mentions: Focal adhesion kinase (FAK) is implicated in the signal transduction of mechanical stress. Two days post-AR, both FAK and pFAK were increased in the LV (Fig. 6a) while it was not the case later at 8 weeks (Fig. 6b). Rapamycin treatment decreased FAK phosphorylation in both sham-operated and AR animals. We also measured the pFAK(Y397)/FAK ratio in stretched HL-1 cells. We observed a strong trend for an increase of FAK phosphorylation (+70 %; p = 0.055) (not shown).Fig. 6

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