Inhibition of Mammalian Target of Rapamycin With Rapamycin Reverses Hypertrophic Cardiomyopathy in Mice With Cardiomyocyte-Specific Knockout of PTEN

Xu, Xihui; Roe, Nathan D.; Weiser‐Evans, Mary C.M.; Ren, Jun

doi:10.1161/hypertensionaha.113.02526

Cited by 41 publications

(55 citation statements)

References 43 publications

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“…Using a pressure overload murine model, Nakai et al (2007) suppressed autophagy 1 week after transverse aortic constriction (TAC) operation. More recent reports also revealed diminished cardiac autophagy or autophagy flux en route to the compromised cardiac function in the face of pressure overload (Marino et al, 2014;Shen et al, 2015;Won Suk Jahng et al, 2015;Xu et al, 2014). Furthermore, Pfeifer et al (1987) found that autophagic vacuoles were significantly decreased to 50% within a 10-min infusion of b-adrenergic agonist isoproterenol.…”

Section: Discussionmentioning

confidence: 92%

“…Dysregulated autophagy has been demonstrated to contribute to the pathogenesis of atherosclerosis, ischemia/reperfusion injury, cardiomyopathy, diabetes mellitus, and hypertension (Ren and Taegtmeyer, 2015;Saito and Sadoshima, 2015). In addition, autophagy is known to participate in the pathogenesis of pressure overload-induced heart diseases (Martinet et al, 2007;Shen et al, 2015;Won Suk Jahng et al, 2015;Xu et al, 2014). Using a pressure overload murine model, Nakai et al (2007) suppressed autophagy 1 week after transverse aortic constriction (TAC) operation.…”

Section: Discussionmentioning

confidence: 99%

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Cardiac-specific overexpression of metallothionein attenuates myocardial remodeling and contractile dysfunction in l-NAME-induced experimental hypertension: Role of autophagy regulation

Yang

Gao

et al. 2015

Toxicology Letters

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Cardiac-specific overexpression of metallothionein attenuates myocardial remodeling and contractile dysfunction in l-NAME-induced experimental hypertension: Role of autophagy regulation

Yang

Gao

et al. 2015

Toxicology Letters

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“…Both in vitro and in vivo studies have suggested that autophagy is involved in the development of cardiomyocyte hypertrophy. 42,43 Several recent studies have shown that statins induced autophagy in mammalian cells, such as human rhabdomyosarcoma cells and PC3 cells. 44,45 More recently, simvastatin was demonstrated to increase autophagy in human airway smooth muscle cells and coronary arterial myocytes.…”

Section: Discussionmentioning

confidence: 99%

Augmentation of autophagy by atorvastatin via Akt/mTOR pathway in spontaneously hypertensive rats

Wang

Qian

et al. 2015

Hypertens Res

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Autophagy is activated in hypertension-induced cardiac hypertrophy. However, the mechanisms and significance of an activated autophagy are not clear. This study was designed to determine the role of atorvastatin (ATO) in cardiac autophagy and associated benefits on cardiac remodeling and left ventricular function in spontaneously hypertensive rats (SHRs). Twenty-eight male SHRs at 8 weeks of age were randomized to treatment with vehicle (saline solution; SHR+V) or ATO (SHR+ATO; 50 mg kg(-1) per day) for 6 or 12 months. Age-matched male Wistar-Kyoto (WKY) rats were used as normotensive controls. Cardiac magnetic resonance was used to evaluate cardiac function and structure. Compared with WKY rats, SHRs showed significant left ventricle (LV) dysfunction, remodeling and increases in cardiomyocyte size, which were all attenuated by 6 and 12 months of ATO treatment. Compared with WKY rats, autophagy was activated in the hearts of SHRs and this effect was amplified by chronic ATO treatment, particularly following 12 months of treatment. Protein expression levels of microtubule-associated protein-1 light chain 3-II and beclin-1, the biomarkers of an activated cardiac autophagy, were significantly elevated in ATO-treated versus vehicle-treated SHRs and control WKY rats. Cardiac Akt and phosphorylated mammalian target of rapamycin (mTOR) expression were also increased in the hearts of SHR versus WKY rats, and this effect was attenuated by ATO treatment. These findings suggest that ATO-mediated improvements in LV function and structure in SHRs may be, in part, through its regulation of cardiac autophagy via the Akt/mTOR pathway.

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“…In addition to preserving Serca2a activity and limiting ER stress, PERK may also exert cardiac protective effects through modulating additional molecular pathways implicated in CHF development. A recent study demonstrated that PERK activation can induce cardiomyocyte autophagy 34 , an evolutionary stress response that is important for adaptation to cardiac stress 35, 36 .…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Sensor Protein Kinase R–Like Endoplasmic Reticulum Kinase (PERK) Protects Against Pressure Overload–Induced Heart Failure and Lung Remodeling

Liu

Kwak

et al. 2014

Hypertension

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Studies have reported that development of congestive heart failure (CHF) is associated with increased endoplasmic reticulum (ER) stress. Double stranded RNA activated protein kinase-like endoplasmic reticulum kinase (PERK) is a major transducer of the ER stress response and directly phosphorylates eIF2α, resulting in translational attenuation. However, the physiological effect of PERK on CHF development is unknown. In order to study the effect of PERK on ventricular structure and function, we generated inducible cardiac specific PERK knockout (KO) mice. Under unstressed conditions, cardiac PERK KO had no effect on left ventricular mass, or its ratio to body weight, cardiomyocyte size, fibrosis, or left ventricular function. However, in response to chronic transverse aortic constriction, PERK KO mice exhibited decreased ejection fraction, increased left ventricular fibrosis, enhanced cardiomyocyte apoptosis and exacerbated lung remodeling in comparison to wild type mice. PERK KO also dramatically attenuated cardiac sarcoplasmic reticulum Ca++-ATPase expression in response to aortic constriction. Our findings suggest that PERK is required to protect the heart from pressure overload-induced CHF.

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Inhibition of Mammalian Target of Rapamycin With Rapamycin Reverses Hypertrophic Cardiomyopathy in Mice With Cardiomyocyte-Specific Knockout of PTEN

Abstract: The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl

Cited by 41 publications

References 43 publications

Cardiac-specific overexpression of metallothionein attenuates myocardial remodeling and contractile dysfunction in l-NAME-induced experimental hypertension: Role of autophagy regulation

Cardiac-specific overexpression of metallothionein attenuates myocardial remodeling and contractile dysfunction in l-NAME-induced experimental hypertension: Role of autophagy regulation

Augmentation of autophagy by atorvastatin via Akt/mTOR pathway in spontaneously hypertensive rats

Endoplasmic Reticulum Stress Sensor Protein Kinase R–Like Endoplasmic Reticulum Kinase (PERK) Protects Against Pressure Overload–Induced Heart Failure and Lung Remodeling

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