Mammalian Target of Rapamycin Is a Critical Regulator of Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Soesanto, Will S.; Lin, Han; Hu, Eric; Lefler, Shane; Litwin, Sheldon E.; Sena, Sandra; Abel, E. Dale; Symons, J. David; Jalili, Thunder

doi:10.1161/hypertensionaha.109.138818

Cited by 80 publications

(78 citation statements)

References 44 publications

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“…These data suggest that the cardiac hypertrophy in Acsl1 TϪ/Ϫ mice was mediated by activation of the mTOR pathway. Possible causes of enhanced mTOR signaling include elevations in amino acid availability (2), enhanced glycolytic flux (41), elevated plasma insulin (21), and hypertension (42). mTOR activation in Acsl1 TϪ/Ϫ hearts probably resulted from a combination of several of these factors, including the 32% higher amino acid content and the increase in glucose uptake and glycolysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Activated mTOR is present in several models of cardiac hypertrophy and is likely to be an important signal in the pathway that mediates hypertrophy. For example, S6K phosphorylation is increased in the hypertrophied hearts of spontaneous hypertensive rats (SHR), and treatment with the mTOR inhibitor rapamycin attenuates the hypertrophy without altering the hypertension (42). Similarly, rapamycin inhibits thyroid hormone-induced S6K phosphorylation and cardiac hypertrophy (25).…”

Section: Discussionmentioning

confidence: 99%

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Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

Ellis

Mentock

DePetrillo

et al. 2011

Molecular and Cellular Biology

165

221

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Long-chain acyl coenzyme A (acyl-CoA) synthetase isoform 1 (ACSL1) catalyzes the synthesis of acyl-CoA from long-chain fatty acids and contributes the majority of cardiac long-chain acyl-CoA synthetase activity. To understand its functional role in the heart, we studied mice lacking ACSL1 globally (Acsl1 T؊/؊ ) and mice lacking ACSL1 in heart ventricles (Acsl1 H؊/؊ ) at different times. Compared to littermate controls, heart ventricular ACSL activity in Acsl1 T؊/؊ mice was reduced more than 90%, acyl-CoA content was 65% lower, and long-chain acyl-carnitine content was 80 to 90% lower. The rate of [ 14 C]palmitate oxidation in both heart homogenate and mitochondria was 90% lower than in the controls, and the maximal rates of [ 14 C]pyruvate and [ 14 C]glucose oxidation were each 20% higher. The mitochondrial area was 54% greater than in the controls with twice as much mitochondrial DNA, and the mRNA abundance of Pgc1␣ and Err␣ increased by 100% and 41%, respectively. Compared to the controls, Acsl1 T؊/؊ and Acsl1 H؊/؊ hearts were hypertrophied, and the phosphorylation of S6 kinase, a target of mammalian target of rapamycin (mTOR) kinase, increased 5-fold. Our data suggest that ACSL1 is required to synthesize the acyl-CoAs that are oxidized by the heart, and that without ACSL1, diminished fatty acid (FA) oxidation and compensatory catabolism of glucose and amino acids lead to mTOR activation and cardiac hypertrophy without lipid accumulation or immediate cardiac dysfunction.The mitochondrial oxidation of long-chain fatty acids (FAs) provides 60 to 90% of heart ATP (9, 43, 49). Reduced cardiac FA oxidation and increased glucose utilization are a proposed consequence of pathological left ventricular hypertrophy (LVH) (22,33). However, when genes that encode enzymes of FA oxidation are knocked out in mice, LVH develops (11,20). Thus, it remains unclear whether the shift in substrate use is a cause or consequence of cardiac hypertrophy and whether the increased use of glucose interferes with cardiac function.Long-chain acyl coenzyme A (acyl-CoA) synthetase (ACSL) isoenzymes convert FAs to acyl coenzyme A (acyl-CoA) in an ATP-dependent manner, simultaneously activating and trapping FAs within cells (4). Activation to acyl-CoA is required before FAs can be either oxidized to provide ATP or esterified to synthesize triacylglycerol (TAG) or membrane phospholipids (PL). The activation of FA is catalyzed by one of a family of five long-chain acyl-CoA synthetases (ACSLs), long-chain acyl-CoA synthetase isoform 1 (ACSL1), ACSL3, ACSL4, ACSL5, and ACSL6, which differ in substrate preference, enzyme kinetics, subcellular location, and tissue-specific expression (10). Because amphipathic acyl-CoAs can move freely within a membrane monolayer or be transported to distant membranes, all acyl-CoAs should, theoretically, be metabolically equivalent, no matter which ACSL isoenzyme catalyzes their formation and no matter which subcellular organelle is the site of their synthesis. Yet, both loss-of-function and gainof-function studies s...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

Ellis

Mentock

DePetrillo

et al. 2011

Molecular and Cellular Biology

165

221

View full text Add to dashboard Cite

show abstract

“…Nevertheless, it also has been used for other purposes, both in animal models and humans. For example, previous studies have demonstrated its efficacy in the treatment of cardiac hypertrophy in spontaneously hypertensive rats (99) and in reducing pressure overload-induced hypertrophy in mice (91,100). Rapamycin also has proven beneficial for treatment of polycystic kidney disease in mice (101,102), a therapy that has moved to clinical trials (103,104), and a rapamycin analog is now approved for the treatment of renal cancer (105).…”

Section: Discussionmentioning

confidence: 99%

Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome–associated PTPN11 mutation

Marin

Keith²,

Davies³

et al. 2011

J. Clin. Invest.

235

270

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LEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11 Y279C/+ (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.

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“…[11][12][13][14][15] However, other studies have challenged the importance of mTOR-mediated protein synthesis and growth. For example, deletion of the ribosomal S6 kinases, direct downstream effectors of mTOR, did not attenuate pathological, physiological, or insulin-like growth factor receptor-induced cardiac hypertrophy.…”

Section: Clinical Perspective On P 1082mentioning

confidence: 99%

Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice

et al. 2011

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Background-Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown. Methods and Results-We generated mice with deficient myocardial mTORC1 activity by targeted ablation of raptor, which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and ␤-myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding-induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed. Conclusions-Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy. (Circulation. 2011;123:1073-1082.)Key Words: heart failure Ⅲ hypertrophy Ⅲ myocardial metabolism Ⅲ signal transduction A lthough cardiac hypertrophy is a growth response that initially normalizes wall tension, it is associated with an unfavorable outcome: Affected patients are threatened with sudden death or progression to heart failure. 1 Much research is therefore aimed at understanding myocardial growth regulation, and in this setting, the insulin-like growth factor/PI3-kinase/Akt signaling cascade has been studied extensively. 2,3 Experiments with cultured cardiomyocytes have suggested that downstream of Akt, mammalian target of rapamycin (mTOR) mediates responses to pathological stimuli. 4,5 mTOR is an evolutionary conserved Ser/Thr kinase known to control cell growth. 6 Nutrient, energy, and growth factor shortage will impair mTOR activity, resulting in diverse effects, including the slowdown of macromolecule synthesis, enhanced autophagy, and activation of nutrient-or stressresponsive transcription factors. mTOR is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. The 2 best-characterized substrates of mTORC1 ...

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Mammalian Target of Rapamycin Is a Critical Regulator of Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Abstract: Abstract-Evidence exists that protein kinase C and the mammalian target of rapamycin are important regulators of cardiac hypertrophy. We examined the contribution of these signaling kinases to cardiac growth in spontaneously hypertensive rats (SHRs

Cited by 80 publications

References 44 publications

Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome–associated PTPN11 mutation

Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice

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