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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

Autophagy markers in LV VO. LC3 and p62 protein contents were evaluated at various times post-AR induction (a, b) as well as the impact of rapamycin treatment (c, d). N = 9–12 animals per group. Values are expressed as mean ± SEM. Means not sharing a common superscript are significantly different from each other, P < 0.05
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Fig7: Autophagy markers in LV VO. LC3 and p62 protein contents were evaluated at various times post-AR induction (a, b) as well as the impact of rapamycin treatment (c, d). N = 9–12 animals per group. Values are expressed as mean ± SEM. Means not sharing a common superscript are significantly different from each other, P < 0.05

Mentions: Autophagy can help eliminate damaged proteins and help survival in cardiac hypertrophy but excessive autophagy may lead to heart failure. mTORC1 is a known regulator of autophagy and we were interested to see if the acute mTORC1 activation in AR LVs could influence this process. We studied the levels of protein markers associated with autophagy namely LC3 and p62/sequestrin. As illustrated in Fig. 7, LV LC3 II levels remained unchanged at the various times post-AR studied. On the other hand, LC3 I levels were more elevated acutely after 2 days post-AR and later in the disease. Rapamycin treatment elevated LC3 I levels in the LVs of AR rats. Moreover, p62 levels were stable after 2 days and 8 weeks (treated or not with rapamycin) but were increased later in the disease.Fig. 7


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)

Autophagy markers in LV VO. LC3 and p62 protein contents were evaluated at various times post-AR induction (a, b) as well as the impact of rapamycin treatment (c, d). N = 9–12 animals per group. Values are expressed as mean ± SEM. 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

Fig7: Autophagy markers in LV VO. LC3 and p62 protein contents were evaluated at various times post-AR induction (a, b) as well as the impact of rapamycin treatment (c, d). N = 9–12 animals per group. Values are expressed as mean ± SEM. Means not sharing a common superscript are significantly different from each other, P < 0.05
Mentions: Autophagy can help eliminate damaged proteins and help survival in cardiac hypertrophy but excessive autophagy may lead to heart failure. mTORC1 is a known regulator of autophagy and we were interested to see if the acute mTORC1 activation in AR LVs could influence this process. We studied the levels of protein markers associated with autophagy namely LC3 and p62/sequestrin. As illustrated in Fig. 7, LV LC3 II levels remained unchanged at the various times post-AR studied. On the other hand, LC3 I levels were more elevated acutely after 2 days post-AR and later in the disease. Rapamycin treatment elevated LC3 I levels in the LVs of AR rats. Moreover, p62 levels were stable after 2 days and 8 weeks (treated or not with rapamycin) but were increased later in the disease.Fig. 7

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