Rad GTPase inhibits cardiac fibrosis through connective tissue growth factor

Ji, Zhang; Chang, Lin; Chen, Chunlei; Zhang, Meiling; Luo, Yan; Hamblin, Milton; Villacorta, Luis; Xiong, Jing Wei; Chen, Y. Eugene; Zhang, Jifeng; Zhu, Xiaojun

doi:10.1093/cvr/cvr068

Cited by 60 publications

(42 citation statements)

References 42 publications

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“…RRAD was also reported to regulate the expression of certain genes. For instance, RRAD was reported to interact with transcription factor C/EBP-δ and inhibit its binding to the promoter of CTGF (connective tissue growth factor), and thus inhibits the expression of CTGF [36]. Therefore, it is possible that RRAD regulates GLUT1 translocation through interaction with proteins and/or regulation of the expression of proteins that are involved in the regulation of GLUT1 translocation.…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD

Zhang

Liu

et al. 2014

Oncotarget

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Cancer cells display enhanced glycolysis to meet their energetic and biosynthetic demands even under normal oxygen concentrations. Recent studies have revealed that tumor suppressor p53 represses glycolysis under normoxia as a novel mechanism for tumor suppression. As the common microenvironmental stress for tumors, hypoxia drives the metabolic switch from the oxidative phosphorylation to glycolysis, which is crucial for survival and proliferation of cancer cells under hypoxia. The p53's role and mechanism in regulating glycolysis under hypoxia is poorly understood. Here, we found that p53 represses hypoxia-stimulated glycolysis in cancer cells through RRAD, a newly-identified p53 target. RRAD expression is frequently decreased in lung cancer. Ectopic expression of RRAD greatly reduces glycolysis whereas knockdown of RRAD promotes glycolysis in lung cancer cells. Furthermore, RRAD represses glycolysis mainly through inhibition of GLUT1 translocation to the plasma membrane. Under hypoxic conditions, p53 induces RRAD, which in turn inhibits the translocation of GLUT1 and represses glycolysis in lung cancer cells. Blocking RRAD by siRNA greatly abolishes p53's function in repressing glycolysis under hypoxia. Taken together, our results revealed an important role and mechanism of p53 in antagonizing the stimulating effect of hypoxia on glycolysis, which contributes to p53's function in tumor suppression.

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Section: Discussionmentioning

confidence: 99%

Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD

Zhang

Liu

et al. 2014

Oncotarget

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“…At the cellular and ex vivo working heart levels, Rad deletion leads to a sympathomimetic positive inotropic contractile state [4]. Rad −/− cardiomyocytes are hypertrophied, and the Rad −/− myocardium displays increased fibrosis [3, 8]. Rad −/− hearts showed no evidence of arrhythmogenesis [4], and Rad deletion preserves systolic heart function well into senescence [3].…”

Section: Introductionmentioning

confidence: 99%

Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart

Levitan

Manning

Withers

et al. 2016

J. of Cardiovasc. Trans. Res.

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Sympathetic stimulation modulates L-type calcium channel (LTCC) gating to contribute to increased systolic heart function. Rad is a monomeric G-protein that interacts with LTCC. Genetic deletion of Rad (Rad−/−) renders LTCC in a sympathomimetic state. The study goal was to use a clinically inspired pharmacological stress echocardiography test, including analysis of global strain, to determine whether Rad−/− confers tonic positive inotropic heart function. Sarcomere dynamics and strain showed partial parallel isoproterenol (ISO) responsiveness for wild-type (WT) and for Rad−/−. Rad−/− basal inotropy was elevated compared to WT but was less responsiveness to ISO. Rad protein levels were lower in human patients with end-stage non-ischemic heart failure. These results show that Rad reduction provides a stable inotropic response rooted in sarcomere level function. Thus, reduced Rad levels in heart failure patients may be a compensatory response to need for increased output in the setting of HF. Rad deletion suggests a future therapeutic direction for inotropic support.

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“…Silencing of Rad expression by siRNA in rat neonatal cardiomyocytes strongly increased protein synthesis and ANF expression, whereas overexpression of Rad significantly reduced PhE-induced protein synthesis and ANF expression, and decreased CaM kinase II activity (73). In vivo, Rad-deficient mice were more susceptible than normal mice to cardiac hypertrophy, with increased CaM kinase II activity (73) and more severe cardiac fibrosis related to an increase in CTGF expression (579). Rad is thus identified as an endogenous cardioprotective mediator that prevents cardiac hypertrophy through the inhibition of CaM kinase II activity and cardiac fibrosis through the inhibition of CTGF.…”

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confidence: 99%

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Loirand

Sauzeau

Pacaud

2013

Physiological Reviews

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Small G proteins exist in eukaryotes from yeast to human and constitute the Ras superfamily comprising more than 100 members. This superfamily is structurally classified into five families: the Ras, Rho, Rab, Arf, and Ran families that control a wide variety of cell and biological functions through highly coordinated regulation processes. Increasing evidence has accumulated to identify small G proteins and their regulators as key players of the cardiovascular physiology that control a large panel of cardiac (heart rhythm, contraction, hypertrophy) and vascular functions (angiogenesis, vascular permeability, vasoconstriction). Indeed, basal Ras protein activity is required for homeostatic functions in physiological conditions, but sustained overactivation of Ras proteins or spatiotemporal dysregulation of Ras signaling pathways has pathological consequences in the cardiovascular system. The primary object of this review is to provide a comprehensive overview of the current progress in our understanding of the role of small G proteins and their regulators in cardiovascular physiology and pathologies.

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Rad GTPase inhibits cardiac fibrosis through connective tissue growth factor

Cited by 60 publications

References 42 publications

Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD

Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD

Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

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