Activating Transcription Factor 3 Deficiency Promotes Cardiac Hypertrophy, Dysfunction, and Fibrosis Induced by Pressure Overload

Zhou, Haoming; Shen, Difei; Bian, Zhou‐Yan; Zong, Jing; Deng, Wei; Zhang, Yan; Guo, Yuanyuan; Li, Hongliang; Tang, Qi‐Zhu

doi:10.1371/journal.pone.0026744

Cited by 74 publications

(74 citation statements)

References 37 publications

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“…This basic ZIP family includes the CREB/ATF family of transcription factors, which include CREB, cAMP response (Kehat et al, 2006). Our study and a prior study by Zhou et al (2011) have shown that ATF3 mRNA levels are upregulated 1 day after TAB procedure and that loss of the ATF3 gene can aggravate pressure overload-induced cardiomyopathy in mice. In addition, we observed that although the nuclear translocation of ATF3 occurred for only a short duration (1 day after TAB procedure), ATF3 protein remained which were transiently cotransfected with indicated plasmids.…”

Section: Discussionsupporting

confidence: 63%

Activating Transcription Factor 3 Protects against Pressure-Overload Heart Failure via the Autophagy Molecule Beclin-1 Pathway

Lin

Chen

et al. 2014

Mol Pharmacol

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Activating transcription factor 3 (ATF3), a cAMP response element-binding protein/ATF family transcription factors member, has been implicated in the cardiovascular and inflammatory system and is rapidly induced by ischemic-reperfusion injuries. We performed transverse aortic banding (TAB) experiments using ATF3 gene-deleted mice (ATF3 2/2 ) and wild-type (WT) mice to determine what effect it might have on heart failure induced by pressure overloading. Compared with the WT mice, ATF3 2/2 mice were found by echocardiography to have decreased left ventricular contractility with loss of normal cardiac hypertrophic remodeling. The ATF3 2/2 mice had greater numbers of terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling-positive cells and higher levels of activated caspase-3, as well as more apoptosis. Restoration of ATF3 expression in the heart of ATF3 2/2 mice by adenovirus-induced ATF3 treatment significantly improved cardiac contractility after TAB. The results from molecular and biochemical analyses, including chromatin immune-precipitation and in vitro /in vivo promoter assays, showed that ATF3 bound to the ATF/cAMP response element of the Beclin-1 promoter and that ATF3 reduced autophagy via suppression of the Beclin-1-dependent pathway. Furthermore, infusion of tert-butylhydroquinone (tBHQ), a selective ATF3 inducer, increased the expression of ATF3 via the nuclear factor erythroid 2-related transcriptional factor, inhibited TABinduced cardiac dilatation, and increased left ventricular contractility, thereby rescuing heart failure. Our study identified a new epigenetic regulation mediated by the stress-inducible gene ATF3 on TAB-induced cardiac dysfunction. These findings suggest that the ATF3 activator tBHQ may have therapeutic potential for the treatment of pressure-overload heart failure induced by chronic hypertension or other pressure overload mechanisms.

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Section: Discussionsupporting

confidence: 63%

Activating Transcription Factor 3 Protects against Pressure-Overload Heart Failure via the Autophagy Molecule Beclin-1 Pathway

Lin

Chen

et al. 2014

Mol Pharmacol

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“…15,16 Cardiac function was determined by transthoracic echocardiography and hemodynamic analysis. 17 Excised hearts were arrested in diastole with 10% KCl, weighed, fixed by perfusion with 10% formalin, and embedded in paraffin for histological studies or were frozen for RNA and protein extraction. Sca-1 expression was determined using Western blotting, immunohistochemistry, and immunofluorescence.…”

Section: Methodsmentioning

confidence: 99%

Stem Cell Antigen 1 Protects Against Cardiac Hypertrophy and Fibrosis After Pressure Overload

Zhou

Bian²,

Zong³

et al. 2012

Hypertension

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Abstract-Stem cell antigen (Sca) 1, a glycosyl phosphatidylinositol-anchored protein localized to lipid rafts, is upregulated in the heart during myocardial infarction and renovascular hypertension-induced cardiac hypertrophy. It has been suggested that Sca-1 plays an important role in myocardial infarction. To investigate the role of Sca-1 in cardiac hypertrophy, we performed aortic banding in Sca-1 cardiac-specific transgenic mice, Sca-1 knockout mice, and their wild-type littermates. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. Sca-1 expression was upregulated and detected in cardiomyocytes after aortic banding surgery in wild-type mice. Sca-1 transgenic mice exhibited significantly attenuated cardiac hypertrophy and fibrosis and preserved cardiac function compared with wild-type mice after 4 weeks of aortic banding. Conversely, Sca-1 knockout dramatically worsened cardiac hypertrophy, fibrosis, and dysfunction after pressure overload. Furthermore, aortic banding-induced activation of Src, mitogen-activated protein kinases, and Akt was blunted by Sca-1 overexpression and enhanced by Sca-1 deficiency. Our results suggest that Sca-1 protects against cardiac hypertrophy and fibrosis via regulation of multiple pathways in cardiomyocytes. Key Words: stem cell antigen 1 Ⅲ cardiac hypertrophy Ⅲ fibrosis Ⅲ Src Ⅲ MAPK Ⅲ Akt C ardiac hypertrophy occurs when the heart experiences elevated workload or injury. Although it is an adaptive response to reduce ventricular wall stress and initially maintain output, sustained hypertrophy leads to ventricular dysfunction and, ultimately, heart failure.1 Left ventricular hypertrophy has been considered to be a maker of increased risk of adverse cardiovascular events.2 The signaling mechanisms involved in the hypertrophic response are complex, including cell surface receptors, signal transduction pathways, and transcriptional and posttranscriptional regulation.3 However, the molecular mechanisms have not been clearly elucidated. A better understanding of the factors that regulate hypertrophic pathways could reveal potential therapeutic targets for treating cardiac hypertrophy and heart failure. Stem cell antigen (Sca) 1 is an 18-kDa glycosyl phosphatidylinositol-anchored protein (GPI-AP) in mice that was originally identified as an antigen upregulated in activated lymphocytes and also named lymphocyte activation protein-6A, as a member of the Ly6 gene family.5 GPI-APs are primarily associated with lipid rafts enriched in sphingolipids and cholesterol, which is important for GPI-APs in signal transduction. 6 The proteins localized in the lipid raft include GPI-APs, Src family kinases, low molecular weight and heterotrimeric G proteins, and various receptor tyrosine kinases. 7,8 Previous studies have shown that inhibition of Sca-1 expression causes the disinhibition of the Src family kinase Fyn, 9 and mutations in Sca-1 and Src family kinases often lead to opposing phenotypes in mice, indicating that Sca-1 serves as a nega...

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“…AB was performed as described previously [12][13][14] ; all of the mice used in our studies were 8-10-week-old males with a body weight of 23.5-27.5 g. Eight weeks following AB, the body weight, heart weight, lung weight and tibial length (TL) of the mice were measured to compare the heart weight/body weight (HW/BW, mg/g), lung weight/body weight (LW/BW, mg/g), and heart weight/TL (HW/TL, mg/mm) ratios.…”

Section: Animals and Animal Modelsmentioning

confidence: 99%

Toll-like receptor 5 deficiency attenuates interstitial cardiac fibrosis and dysfunction induced by pressure overload by inhibiting inflammation and the endothelial–mesenchymal transition

Liu

Liao

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Vascular dysfunction, characterized by the endothelial-to-mesenchymal transition (EndMT), contributes to the development of cardiac fibrosis induced by pressure overload. Toll-like receptor (TLR)5 is a member of the TLR family that is expressed on not only immune cells but also nonimmune cells including cardiomyocytes and vascular endothelial cells. The level of TLR5 expression on endothelial cells is low under normal circumstances but is increased in response to stimuli such as pressure overload. The aim of this study was to investigate the importance of TLR5 in cardiac endothelial dysfunction during the development of cardiac fibrosis induced by pressure overload. Global TLR5-deficient mice and wild-type littermates underwent aortic banding (AB) for 8weeks to induce cardiac fibrosis, hypertrophy and dysfunction. The deficiency of TLR5 in this model exerted no basal effects but attenuated the cardiac fibrosis, hypertrophy and dysfunction induced by pressure overload. AB-induced endothelial TLR5 activation enhanced the development of cardiac fibrosis independent of cardiomyocyte hypertrophy and triggered left ventricular dysfunction. TLR5-deficient mice also exhibited ameliorated myocardial pro-inflammatory cytokine expression and macrophage infiltration and inhibited the EndMT, all of which contribute to the development of cardiac fibrosis. These findings suggest that TLR5 triggers inflammatory responses and promotes the EndMT, which may be an important mechanism underlying the promotion of cardiac fibrosis and left ventricular dysfunction during pressure overload.

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Activating Transcription Factor 3 Deficiency Promotes Cardiac Hypertrophy, Dysfunction, and Fibrosis Induced by Pressure Overload

Cited by 74 publications

References 37 publications

Activating Transcription Factor 3 Protects against Pressure-Overload Heart Failure via the Autophagy Molecule Beclin-1 Pathway

Activating Transcription Factor 3 Protects against Pressure-Overload Heart Failure via the Autophagy Molecule Beclin-1 Pathway

Stem Cell Antigen 1 Protects Against Cardiac Hypertrophy and Fibrosis After Pressure Overload

Toll-like receptor 5 deficiency attenuates interstitial cardiac fibrosis and dysfunction induced by pressure overload by inhibiting inflammation and the endothelial–mesenchymal transition

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