Inhibition of mTOR Signaling With Rapamycin Regresses Established Cardiac Hypertrophy Induced by Pressure Overload

McMullen, Julie R.; Sherwood, Megan C.; Tarnavski, Oleg; Zhang, Li; Dorfman, Adam L.; Shioi, Tetsuo; Izumo, Seigo

doi:10.1161/01.cir.0000130641.08705.45

Cited by 455 publications

(404 citation statements)

References 19 publications

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“…Moreover, rapamycin was able to regress already established cardiac hypertrophy and reversed characteristic features of maladaption, i.e. LV dilation and contractile dysfunction [39]. In this regard it is remarkable that in the current study we demonstrate that in cardiac myocytes celecoxib inhibits the phosphorylation of GSK-3β and mTOR-regulated S6K.…”

Section: Discussionsupporting

confidence: 66%

Celecoxib modulates hypertrophic signalling and prevents load‐induced cardiac dysfunction

Jacobshagen

Grüber

Teucher

et al. 2008

European J of Heart Fail

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In human hearts, the transition from cardiac hypertrophy to advanced heart failure (HF) is accompanied by a tremendous increase in Akt phosphorylation. In non-myocardial tissue, the cyclooxygenase (COX)-2 inhibitor celecoxib has been shown to COX-independently inhibit Akt signalling.We studied the effects of celecoxib on Akt signalling and hypertrophic response in myocardium. In rabbit isolated cardiac myocytes celecoxib concentration-dependently (10-100 μmol/L) inhibited the insulin-induced increase in phosphorylation of Akt and its downstream targets, GSK-3β and p70 S6 kinase, by reducing the phosphorylation level of the upstream regulator PTEN. Inhibition of Akt signalling was accompanied by a significant suppression of characteristic features of cardiac hypertrophy: Celecoxib concentration-dependently suppressed the agonist-induced enhancement of total protein synthesis and BNP mRNA expression.In mice (C57BL/6NCrl) subjected to left ventricular (LV) pressure overload by aortic banding, celecoxib treatment (50 mg•kg − 1 •d − 1 ) significantly attenuated LV dilation and contractile dysfunction compared with placebo-treated mice. Moreover, celecoxib significantly reduced mortality 8 weeks after banding.Thus, celecoxib can be used to titrate Akt signalling and hypertrophic response in myocardium. It reduces load-induced LV dilation, contractile dysfunction and mortality in vivo. This may have clinical implications for the prevention and treatment of maladaptive hypertrophy and its progression to HF in humans.

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Section: Discussionsupporting

confidence: 66%

Celecoxib modulates hypertrophic signalling and prevents load‐induced cardiac dysfunction

Jacobshagen

Grüber

Teucher

et al. 2008

European J of Heart Fail

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“…29 Rapamycin, a potent activator of autophagy, prevents cardiac hypertrophy induced by thyroid hormone treatment, 35 or aortic banding, 36 and regresses existing cardiac hypertrophy. 37 These suggest that a decrease in autophagy at the hypertrophied state facilitates cardiac hypertrophic response. However, cardiac hypertrophic response is similar between cardiac-specific Atg5-deficient mice and the control mice after TAC, suggesting that autophagy does not play a role in regulating the cardiomyocyte hypertrophy induced by pressure overload or that its function in the hypertrophic process is compensated by the action of other hypertrophic signaling mechanisms.…”

Section: Autophagy In Cardiac Hypertrophymentioning

confidence: 99%

The role of autophagy in the heart

Kyoi²,

et al. 2008

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Autophagy has evolved as a conserving process that uses bulk degradation and recycling of cytoplasmic components, such as long-lived proteins and organelles. In the heart, autophagy is important for the turnover of organelles at low basal levels under normal conditions and it is upregulated in response to stresses such as ischemia/reperfusion and in cardiovascular diseases such as heart failure. Cardiac remodeling involves increased rates of cardiomyocyte cell death and precedes heart failure. The simultaneously occurring multiple features of failing hearts include not only apoptosis and necrosis but also autophagy as well. However, it has been unclear as to whether autophagy is a sign of failed cardiomyocyte repair or is a suicide pathway for failing cardiomyocytes. The functional role of autophagy during ischemia/reperfusion in the heart is complex. It has also been unclear whether autophagy is protective or detrimental in response to ischemia/reperfusion in the heart. In this review, we will summarize the role of autophagy in the heart under both normal conditions and in response to stress.

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“…Both strategies probably rely on a delicate degree of modulation. For example, mitigation of protein synthesis by partial inhib ition of mechanistic target of rapamycin (mTOR), by rapamycin or resveratrol, reversed cardiac hyper trophy and impaired cardiac function in aortic banded mice 176 and protected against myocardial infarction induced HF 177 . Likewise, rapamycin improved cardiac function in DCM in Lmna −/− mice 178 .…”

Section: Pharmacological Modulation Of Pqcmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

137

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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Inhibition of mTOR Signaling With Rapamycin Regresses Established Cardiac Hypertrophy Induced by Pressure Overload

Cited by 455 publications

References 19 publications

Celecoxib modulates hypertrophic signalling and prevents load‐induced cardiac dysfunction

Celecoxib modulates hypertrophic signalling and prevents load‐induced cardiac dysfunction

The role of autophagy in the heart

Proteostasis in cardiac health and disease

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