Genetic and Pharmacological Inhibition of Rheb1-mTORC1 Signaling Exerts Cardioprotection against Adverse Cardiac Remodeling in Mice

Wu, Xiangqi; Cao, Yunshan; Nie, Junwei; Liu, Hailang; Lu, Shuangshuang; Hu, Xiaoshan; Zhu, Jingai; Zhao, Xia; Chen, Jiandong; Chen, Xiaohu; Yang, Zhongzhou; Li, Xinli

doi:10.1016/j.ajpath.2013.02.012

Cited by 62 publications

(63 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The TAC or sham surgery described previously was performed 14. Briefly, C57BL/6 male mice (aged 7 weeks; Fourth Military Medical University Medical Laboratory Animal Center, Xi'an, People's Republic of China) were anesthetized with a mixture of ketamine and xylazine.…”

Section: Methodsmentioning

confidence: 99%

Mitogen‐Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation–Induced Cardiac Hypertrophy

Chen

Xin

Liu

et al. 2016

JAHA

View full text Add to dashboard Cite

BackgroundThe transient receptor potential vanilloid type 1 (TRPV1) is expressed in the cardiovascular system, and increased TRPV1 expression has been associated with cardiac hypertrophy. Nevertheless, the role of TRPV1 in the pathogenesis of cardiac hypertrophy and the underlying molecular mechanisms remain unclear.Methods and ResultsIn cultured cardiomyocytes, activation of TRPV1 increased cell size and elevated expression of atrial natriuretic peptide mRNA and intracellular calcium level, which was reversed by TRPV1 antagonist capsazepine. Increased expression of phosphorylated calmodulin‐dependent protein kinase IIδ and mitogen‐activated protein kinases were found in TRPV1 agonist capsaicin‐treated cardiomyocytes. Selective inhibitor of calmodulin‐dependent protein kinase IIδ decreased phosphorylation of extracellular signal–regulated kinases and p38. Capsaicin induced an increase in expression of ornithine decarboxylase protein, which is the key enzyme in polyamine biosynthesis in cardiomyocytes. Nevertheless, there was no obvious change of ornithine decarboxylase expression in TRPV1 knockdown cells after capsaicin treatment, and specific inhibitors of calmodulin‐dependent protein kinase IIδ or p38 downregulated the capsaicin‐induced expression of ornithine decarboxylase. Capsazepine alleviated the increase in cross‐sectional area of cardiomyocytes and the ratio of heart weight to body weight and improved cardiac function, including left ventricular internal end‐diastolic and ‐systolic dimensions and ejection fraction and fractional shortening percentages, in mice treated with transverse aorta constriction. Capsazepine also reduced expression of ornithine decarboxylase and cardiac polyamine levels. Transverse aorta constriction induced increases in phosphorylated calmodulin‐dependent protein kinase IIδ and extracellular signal–regulated kinases, and p38 and Serca2a were attenuated by capsazepine treatment.ConclusionsThis study revealed that the mitogen‐activated protein kinase signaling pathway and intracellular polyamines are essential for TRPV1 activation–induced cardiac hypertrophy.

show abstract

Section: Methodsmentioning

confidence: 99%

Mitogen‐Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation–Induced Cardiac Hypertrophy

Chen

Xin

Liu

et al. 2016

JAHA

View full text Add to dashboard Cite

show abstract

“…ApoE –/– mice are more susceptible to cardiac hypertrophy and dysfunction [10, 30]. Compared with age-matched wild-type mice, ApoE –/– mice had an increased total ventricular weight, left ventricular weight and HW/BW ratio, a larger LV end diastolic dimension and a smaller LVEF [10, 11, 30].…”

Section: Discussionmentioning

confidence: 99%

“…AST-IV attenuated LPS-induced cardiac hypertrophy through inhibiting the activation of Ca 2+ /calcineurin, GATA-4, and the nuclear translocation of NFAT-3 [27]. AST-IV strongly blocked Rheb/mTORC1 signaling pathway and reduced its downstream phospho-S6K levels in myocardial infarction (MI) and transverse aortic constriction (TAC) mice model [30]. AST-IV has shown the ability to attenuate oxidative stress and suppress the activation of the mitochondrial apoptosis via PI3K/Akt signaling pathway [32].…”

Section: Discussionmentioning

confidence: 99%

“…Over-stimulation of mTORC1 pathway through growth factors promoted cardiac senescence. Previous studies proved that AST-IV could resist the cardiac adrenergic [28] and angiotensin stimulation [56], inhibit mTORC1 [30], and thus protect against cardiac remodeling. In this study, we found that the hypercholesterolemic heart presented high expressions of p16 and p53, which could be reversed after AST-IV treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Bge , which is a traditional Chinese herb widely used in clinical practice and has been demonstrated to be effective in treating various diseases [22, 23], including cardiovascular diseases [24, 25]. AST-IV possesses diverse cardiovascular protective properties against cardiac hypertrophy [26-30], cardiomyocyte apoptosis [29-33], myocardial fibrosis [30, 34-36], oxidative stress [31, 37] and so on.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Astragaloside IV Prevents Cardiac Remodeling in the Apolipoprotein E-Deficient Mice by Regulating Cardiac Homeostasis and Oxidative Stress

Ding²,

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: Hypercholesterolemia is a risk factor for the development of cardiac hypertrophy. Astragaloside IV (AST-IV) possesses cardiovascular protective properties. We hypothesize that AST-IV prevents cardiac remodeling with hypercholesterolemia via modulating tissue homeostasis and alleviating oxidative stress. Methods: The ApoE^-/- mice were treated with AST-IV at 1 or 10 mg/kg for 8 weeks. The blood lipids tests, echocardiography, and TUNEL were performed. The mRNA expression profile was detected by real-time PCR. The myocytes size and number, and the expressions of proliferation (ki67), senescence (p16^INK4a), oxidant (NADPH oxidase 4, NOX4) and antioxidant (superoxide dismutase, SOD) were observed by immunofluorescence staining. Results: Neither 1 mg/kg nor 10 mg/kg AST-IV treatment could decrease blood lipids in ApoE^-/- mice. However, the decreased left ventricular ejection fraction (LVEF) and fractional shortening (FS) in ApoE^–/– mice were significantly improved after AST-IV treatment. The cardiac collagen volume fraction declined nearly in half after AST-IV treatment. The enlarged myocyte size was suppressed, and myocyte number was recovered, and the alterations of genes expressions linked to cell cycle, proliferation, senescence, p53-apoptosis pathway and oxidant-antioxidants in the hearts of ApoE^-/- mice were reversed after AST-IV treatment. The decreased ki67 and increased p16^INK4a in the hearts of ApoE^-/- mice were recovered after AST-IV treatment. The percentages of apoptotic myocytes and NOX4-positive cells in AST-IV treated mice were decreased, which were consistent with the gene expressions. Conclusion: AST-IV treatment could prevent cardiac remodeling and recover the impaired ventricular function induced by hypercholesterolemia. The beneficial effect of AST-IV might partly be through regulating cardiac homeostasis and anti-oxidative stress.

show abstract

The alteration of protein prenylation induces cardiomyocyte hypertrophy through Rheb–mTORC1 signalling and leads to chronic heart failure

Guan

Chen

et al. 2015

The Journal of Pathology

View full text Add to dashboard Cite

G protein-regulated cell function is crucial for cardiomyocytes, and any deregulation of its gene expression or protein modification can lead to pathological cardiac hypertrophy. Herein, we report that protein prenylation, a lipidic modification of G proteins that facilitates their association with the cell membrane, might control the process of cardiomyocyte hypertrophy. We found that geranylgeranyl diphosphate synthase (GGPPS), a key enzyme involved in protein prenylation, played a critical role in postnatal heart growth by regulating cardiomyocyte size. Cardiac-specific knockout of GGPPS in mice led to spontaneous cardiac hypertrophy, beginning from week 4, accompanied by the persistent enlargement of cardiomyocytes. This hypertrophic effect occurred by altered prenylation of G proteins. Evaluation of the prenylation, membrane association and hydrophobicity showed that Rheb was hyperactivated and increased mTORC1 signalling pathway after GGPPS deletion. Protein farnesylation or mTORC1 inhibition blocked GGPPS knockdown-induced mTORC1 activation and suppressed the larger neonatal rat ventricle myocyte size and cardiomyocyte hypertrophy in vivo, demonstrating a central role of the FPP-Rheb-mTORC1 axis for GGPPS deficiency-induced cardiomyocyte hypertrophy. The sustained cardiomyocyte hypertrophy progressively provoked cardiac decompensation and dysfunction, ultimately causing heart failure and adult death. Importantly, GGPPS was down-regulated in the hypertrophic hearts of mice subjected to transverse aortic constriction (TAC) and in failing human hearts. Moreover, HPLC-MS/MS detection revealed that the myocardial farnesyl diphosphate (FPP):geranylgeranyl diphosphate (GGPP) ratio was enhanced after pressure overload. Our observations conclude that the alteration of protein prenylation promotes cardiomyocyte hypertrophic growth, which acts as a potential cause for pathogenesis of heart failure and may provide a new molecular target for hypertrophic heart disease clinical therapy.

show abstract

Genetic and Pharmacological Inhibition of Rheb1-mTORC1 Signaling Exerts Cardioprotection against Adverse Cardiac Remodeling in Mice

Cited by 62 publications

References 25 publications

Mitogen‐Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation–Induced Cardiac Hypertrophy

Mitogen‐Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation–Induced Cardiac Hypertrophy

Astragaloside IV Prevents Cardiac Remodeling in the Apolipoprotein E-Deficient Mice by Regulating Cardiac Homeostasis and Oxidative Stress

The alteration of protein prenylation induces cardiomyocyte hypertrophy through Rheb–mTORC1 signalling and leads to chronic heart failure

Contact Info

Product

Resources

About