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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

Rapamycin reduces LV and RV hypertrophy and cardiac myocytes hypertrophy in AR rats. a LV and right ventricle (RV) weight after 8-week VO from AR and LV cardiac myocytes cross-sectional area (CSA) evaluated in mid-LV sections stained with Trichrome-Masson. b, c Representative Trichrome-Masson LV sections at different magnifications (b: bar = 1 cm and c: X200). For CSA, three sections per animals were analyzed and at least 20 myocytes per section measured by an observer blinded for the groups. n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05
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Fig1: Rapamycin reduces LV and RV hypertrophy and cardiac myocytes hypertrophy in AR rats. a LV and right ventricle (RV) weight after 8-week VO from AR and LV cardiac myocytes cross-sectional area (CSA) evaluated in mid-LV sections stained with Trichrome-Masson. b, c Representative Trichrome-Masson LV sections at different magnifications (b: bar = 1 cm and c: X200). For CSA, three sections per animals were analyzed and at least 20 myocytes per section measured by an observer blinded for the groups. n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05

Mentions: AR caused severe heart hypertrophy. Rapamycin treatment significantly reduced LVH in AR rats (Table 1). Rapamycin treatment had no impact on heart weight in sham-operated animals. A similar pattern was observed also for both left and the right ventricles in AR animals where rapamycin inhibited hypertrophy by 41 and 49 %, respectively (p < 0.01 for both) (Fig. 1a, b). Myocytes cross-sectional area was larger in the untreated AR group compared to healthy rats (+46 %; p < 0.001). Rapamycin reversed this increase by 67 % (p < 0.05; Fig. 1a, c). We did not notice any significant accumulation of interstitial or perivascular fibrosis in AR animals at 8 weeks (Fig. 1c). As expected and previously reported by others, body weight was lower in the animals treated with rapamycin probably related with decreased food intake (34 g/day, untreated vs. 28, rapa; p = 0.03) leading to a lower adipose tissue mass (Festuccia et al. 2014; Blanchard et al. 2012). Tibial length (an index of body growth) was only slightly reduced (1 %; p = 0.006) by rapamycin suggesting that treated animals were just leaner (Table 1). Echocardiographic data at the end of the protocol are also summarized in Table 1. As expected, AR resulted in significant end-diastolic and end-systolic LV dilatation. Ejection fraction was lower in AR animals. Rapamycin treatment in AR significantly reduced end-diastolic and end-systolic diameters compared to untreated AR. AR severity was similar in both AR groups.Table 1


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)

Rapamycin reduces LV and RV hypertrophy and cardiac myocytes hypertrophy in AR rats. a LV and right ventricle (RV) weight after 8-week VO from AR and LV cardiac myocytes cross-sectional area (CSA) evaluated in mid-LV sections stained with Trichrome-Masson. b, c Representative Trichrome-Masson LV sections at different magnifications (b: bar = 1 cm and c: X200). For CSA, three sections per animals were analyzed and at least 20 myocytes per section measured by an observer blinded for the groups. 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

Fig1: Rapamycin reduces LV and RV hypertrophy and cardiac myocytes hypertrophy in AR rats. a LV and right ventricle (RV) weight after 8-week VO from AR and LV cardiac myocytes cross-sectional area (CSA) evaluated in mid-LV sections stained with Trichrome-Masson. b, c Representative Trichrome-Masson LV sections at different magnifications (b: bar = 1 cm and c: X200). For CSA, three sections per animals were analyzed and at least 20 myocytes per section measured by an observer blinded for the groups. n = 9–12. Means not sharing a common superscript are significantly different from each other, P < 0.05
Mentions: AR caused severe heart hypertrophy. Rapamycin treatment significantly reduced LVH in AR rats (Table 1). Rapamycin treatment had no impact on heart weight in sham-operated animals. A similar pattern was observed also for both left and the right ventricles in AR animals where rapamycin inhibited hypertrophy by 41 and 49 %, respectively (p < 0.01 for both) (Fig. 1a, b). Myocytes cross-sectional area was larger in the untreated AR group compared to healthy rats (+46 %; p < 0.001). Rapamycin reversed this increase by 67 % (p < 0.05; Fig. 1a, c). We did not notice any significant accumulation of interstitial or perivascular fibrosis in AR animals at 8 weeks (Fig. 1c). As expected and previously reported by others, body weight was lower in the animals treated with rapamycin probably related with decreased food intake (34 g/day, untreated vs. 28, rapa; p = 0.03) leading to a lower adipose tissue mass (Festuccia et al. 2014; Blanchard et al. 2012). Tibial length (an index of body growth) was only slightly reduced (1 %; p = 0.006) by rapamycin suggesting that treated animals were just leaner (Table 1). Echocardiographic data at the end of the protocol are also summarized in Table 1. As expected, AR resulted in significant end-diastolic and end-systolic LV dilatation. Ejection fraction was lower in AR animals. Rapamycin treatment in AR significantly reduced end-diastolic and end-systolic diameters compared to untreated AR. AR severity was similar in both AR groups.Table 1

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