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. Author manuscript; available in PMC: 2019 Mar 4.
Published in final edited form as: Circ Res. 2018 Feb 2;122(3):489–505. doi: 10.1161/CIRCRESAHA.117.311147

Table 1.

Cardiac effects of genetic and pharmacological mTOR modulation during development, physiology and stress.

Cardiac condition mTOR modulation/ animal model Cellular modifications and cardiac outcomes Reference
Development/physiological conditions Constitutive cardiac mTOR gene deletion ↑ Early mortality, heart failure, cardiac dilatation, cardiac dysfunction 14
Constitutive cardiac rictor gene deletion ↓ Cardiac function over time 19
Inducible cardiac mTOR gene deletion during adulthood ↑ Apoptosis, mitochondrial dysfunction, autophagy, sarcomere disarray
↓ Protein synthesis
↑ Early mortality, heart failure, cardiac dilatation, cardiac dysfunction
15,16
Constitutive cardiac mTOR gene deletion at early post-natal stage ↑ Apoptosis
↓ Protein synthesis
↑ Early mortality, hypoxia, cardiac dilatation
39
Constitutive cardiac Rheb gene deletion ↓ Protein synthesis
↑ Early mortality, heart failure, cardiac growth, cardiac dysfunction
17
Aging mTOR inhibition using rapamycin ↑ Energy metabolism
↓ Heart inflammation, cardiac fibrosis
22
Systemic GSK-3α gene deletion ↓ Autophagy
↑ Sarcomere disarray
↑ Early mortality, cardiac hypertrophy, cardiac dysfunction during aging
107
Cardiac hypertrophy Inducible cardiac mTOR gene deletion during adulthood and pressure overload ↓ Protein synthesis
↓ Compensatory hypertrophy
↑ Cardiac dysfunction, heart failure
15,16
mTOR inhibition using rapamycin and pressure overload ↑ Cardiac function
↓ Cardiac hypertrophy
110
mTOR inhibition using rapamycin and TAC ↓ Cardiac hypertrophy, cardiac dysfunction 113
mTOR inhibition using Akt inhibitor and volume overload ↓ Eccentric hypertrophy 114
Constitutive heterozygous cardiac Rheb gene deletion and pressure overload ↓ Cardiac hypertrophy, cardiac fibrosis 23
Cardiac PRAS40 overexpression and pressure overload ↓ Cardiac hypertrophy, cardiac fibrosis
↑ Cardiac function
115
Systemic TSC1 overexpression and isoproterenol administration ↓ Cardiac hypertrophy
↑ Cardiac function
116
Epigenetic mTOR inhibition and pressure overload ↓ Cardiac hypertrophy
↑ Cardiac function
119,120
Constitutive cardiac rictor gene deletion and pressure overload ↑ Apoptosis
↑ Cardiac dilatation
↓ Compensatory hypertrophy
19
Inducible cardiac rictor gene deletion during adulthood and pressure overload ↑ Cardiac dysfunction, cardiac dilatation 18
Ischemic injury Cardiac Rheb overexpression during prolonged ischemia ↓ Autophagy
↑ Apoptosis
↑ Infarct size
59
Cardiac dominant negative GSK-3β overexpression and systemic heterozygous GSK-3β deletion during prolonged ischemia ↓ Autophagy
↑ Ischemic injury
84
Cardiac PRAS40 overexpression during chronic myocardial infarction ↓ Apoptosis
↓ Ischemic injury, cardiac remodeling
↑ Cardiac function
20
mTOR inhibition using everolimus and chronic myocardial infarction ↑ Autophagy
↓ Cardiac remodeling, infarct size, cardiac dilatation
↑ Cardiac function
25
mTOR inhibition using rapamycin and S6K inhibitor and myocardial infarction ↓ Apoptosis
↓ Ischemic injury
128
Cardiac rictor gene deletion and myocardial infarction ↑ Cardiac remodeling, cardiac dysfunction 20
Cardiac dominant negative GSK-3β overexpression and systemic heterozygous GSK-3β deletion and I/R ↓ Reperfusion injury 84
Genetic disorders mTOR inhibition using rapamycin in a model of cardiomyopathy caused by mutation in Laminin A/C gene ↑ Autophagy
↓ Cardiac remodeling
↑ Cardiac function
54,138
mTOR inhibition using rapamycin in a mouse model of LEOPARD syndrome ↓ Cardiac hypertrophy, myocardial disarray 136
Metabolic disorders mTOR inhibition using rapamycin in high-fat diet-induced obesity ↑ Autophagy
↑ Cardiac function
141
Systemic Akt2 knockout in high-fatdiet-induced obesity ↑ Autophagy
↑ Cardiac function
142
mTOR inhibition using rapamycin in type II diabetic mice ↓ Plasma glucose, triglyceride levels, oxidative stress
↑ Cardiac function
145
Cardiac PRAS40 overexpression in diabetic mice ↑ Metabolic function, cardiac function
↓ Cardiac hypertrophy
146

Legend: Akt, protein kinase B; GSK, glycogen synthase kinase; I/R, ischemia/reperfusion; mTOR, mechanistic target of rapamycin; PRAS40, proline-rich Akt substrate 40; Rheb, Ras homolog enriched in brain; rictor, rapamycin insensitive companion of mTOR; S6K, S6 kinase; TAC, transverse aortic constriction; TSC1, tuberous sclerosis protein 1.

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