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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

Hypertrophic markers expression in AR rats. LV mRNA levels of natriuretic peptides (ANP and BNP; top row), myosin heavy chains (α and β; middle row) and collagens (Type I and III, bottom row) were evaluated as described in “Methods” section. White columns: untreated groups (ctrl); black columns: rapamycin groups (rapa). n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05
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Fig3: Hypertrophic markers expression in AR rats. LV mRNA levels of natriuretic peptides (ANP and BNP; top row), myosin heavy chains (α and β; middle row) and collagens (Type I and III, bottom row) were evaluated as described in “Methods” section. White columns: untreated groups (ctrl); black columns: rapamycin groups (rapa). n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05

Mentions: The relative expression of ANP and BNP mRNAs were measured in LV tissues. Results are reported in Fig. 3. All AR groups at 8 weeks displayed a significant increase in ANP and BNP mRNA expression. BNP mRNA levels were significantly decreased by rapamycin treatment in AR animals. The same was true for the pro-hypertrophic TRPC6 gene (not shown). Myosin heavy chains (MHC) mRNA levels were also measured. The αMHC mRNA levels were lower in the AR groups whereas βMHC mRNA levels remained stable. Rapamycin did not significantly affect these levels. Collagen type I mRNA levels were higher in untreated AR animals but rapamycin reversed this increase. Collagen type III mRNA levels were not regulated.Fig. 3


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)

Hypertrophic markers expression in AR rats. LV mRNA levels of natriuretic peptides (ANP and BNP; top row), myosin heavy chains (α and β; middle row) and collagens (Type I and III, bottom row) were evaluated as described in “Methods” section. White columns: untreated groups (ctrl); black columns: rapamycin groups (rapa). 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

Fig3: Hypertrophic markers expression in AR rats. LV mRNA levels of natriuretic peptides (ANP and BNP; top row), myosin heavy chains (α and β; middle row) and collagens (Type I and III, bottom row) were evaluated as described in “Methods” section. White columns: untreated groups (ctrl); black columns: rapamycin groups (rapa). n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05
Mentions: The relative expression of ANP and BNP mRNAs were measured in LV tissues. Results are reported in Fig. 3. All AR groups at 8 weeks displayed a significant increase in ANP and BNP mRNA expression. BNP mRNA levels were significantly decreased by rapamycin treatment in AR animals. The same was true for the pro-hypertrophic TRPC6 gene (not shown). Myosin heavy chains (MHC) mRNA levels were also measured. The αMHC mRNA levels were lower in the AR groups whereas βMHC mRNA levels remained stable. Rapamycin did not significantly affect these levels. Collagen type I mRNA levels were higher in untreated AR animals but rapamycin reversed this increase. Collagen type III mRNA levels were not regulated.Fig. 3

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