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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

mTORC1 is transiently activated in LV VO. Protein content of the phosphorylated (p) and total forms of S6 and Akt (Ser473) in the LV of AR rats two days and 6 months post-surgery. a Characteristics of AR rats after 2 days or 6 months. b, c LV protein contents of 2-Day and 6-month AR rats. d, e Representative blots. n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05
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Fig4: mTORC1 is transiently activated in LV VO. Protein content of the phosphorylated (p) and total forms of S6 and Akt (Ser473) in the LV of AR rats two days and 6 months post-surgery. a Characteristics of AR rats after 2 days or 6 months. b, c LV protein contents of 2-Day and 6-month AR rats. d, e Representative blots. n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05

Mentions: Since AR did not seem to modulate the different members of the mTOR signaling pathway studied at 8 weeks, we measured in LV crude homogenates the contents of ribosomal S6 protein as an index of mTORC1 activity and AKT (S473) as an index of mTORC2 activity at other stages of the disease (Volkers et al. 2013a). Two days of severe volume overload (>70 % regurgitation) were sufficient to initiate a hypertrophic response in AR rats as illustrated by the small but significant increase in LV weight (Fig. 4a). S6 phosphorylation was strongly increased in the LVs of AR rats 2 days post-AR induction while pAKT levels remained stable (Fig. 4b, d). A trend for a similar pattern was also present 6 month post-AR in the LV of surviving animals (15 out of 20) although the pS6/S6 ratio remained unchanged (Fig. 4c, e).Fig. 4


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)

mTORC1 is transiently activated in LV VO. Protein content of the phosphorylated (p) and total forms of S6 and Akt (Ser473) in the LV of AR rats two days and 6 months post-surgery. a Characteristics of AR rats after 2 days or 6 months. b, c LV protein contents of 2-Day and 6-month AR rats. d, e Representative blots. 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

Fig4: mTORC1 is transiently activated in LV VO. Protein content of the phosphorylated (p) and total forms of S6 and Akt (Ser473) in the LV of AR rats two days and 6 months post-surgery. a Characteristics of AR rats after 2 days or 6 months. b, c LV protein contents of 2-Day and 6-month AR rats. d, e Representative blots. n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05
Mentions: Since AR did not seem to modulate the different members of the mTOR signaling pathway studied at 8 weeks, we measured in LV crude homogenates the contents of ribosomal S6 protein as an index of mTORC1 activity and AKT (S473) as an index of mTORC2 activity at other stages of the disease (Volkers et al. 2013a). Two days of severe volume overload (>70 % regurgitation) were sufficient to initiate a hypertrophic response in AR rats as illustrated by the small but significant increase in LV weight (Fig. 4a). S6 phosphorylation was strongly increased in the LVs of AR rats 2 days post-AR induction while pAKT levels remained stable (Fig. 4b, d). A trend for a similar pattern was also present 6 month post-AR in the LV of surviving animals (15 out of 20) although the pS6/S6 ratio remained unchanged (Fig. 4c, e).Fig. 4

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