scholarly journals A multi-network comparative analysis of transcriptome and translatome in cardiac remodeling

2020 ◽  
Author(s):  
Etienne Boileau ◽  
Shirin Doroudgar ◽  
Eva Riechert ◽  
Lonny Jürgensen ◽  
Thanh Cao Ho ◽  
...  
Keyword(s):  
Comparative Analysis ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Functional Modules ◽  
Hub Genes ◽  
Pathological Cardiac Hypertrophy ◽  
Altered Gene

Our understanding of the transition from physiological to pathological cardiac hypertrophy remains elusive and largely based on reductionist hypotheses. Here, we profiled the translatomes of 15 mouse hearts to provide a molecular blueprint of altered gene networks in early cardiac remodeling. Using co-expression analysis, we reveal how sub-networks are orchestrated into functional modules associated with pathological phenotypes. We show how transcriptome networks are only partially reproducible at the translatome level. We find unappreciated hub genes and genes in the transcriptional network that were rewired in the translational network, and associated with semantically different subsets of enriched functional terms, providing novel insights into the complexity of the organization of in vivo cardiac regulatory networks.

Pygo1 regulates pathological cardiac hypertrophy via a β-catenin-dependent mechanism

2021 ◽  
Author(s):  
Li Lin ◽  
Wei Xu ◽  
Yongqing Li ◽  
Ping Zhu ◽  
Wuzhou Yuan ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Tissue ◽  
Heart Weight ◽  
Dependent Manner ◽  
Tissue Specific ◽  
Cardiac Tissues ◽  
Pathological Cardiac Hypertrophy ◽  
Interaction Factor ◽  
Myocardial Remodelling

Wnt/β-catenin signalling plays a key role in pathological cardiac remodelling in adults. The identification of a tissue-specific Wnt/β-catenin interaction factor may realise a tissue-specific clinical targeting strategy. Drosophila Pygo codes for the core interaction factor of Wnt/β-catenin. Two Pygo homologs, Pygo1 and Pygo2, have been identified in mammals. Different from the ubiquitous expression profile of Pygo2, Pygo1is enriched in cardiac tissue. However, the role of Pygo1 in mammalian cardiac disease remains unelucidated. Here, we found that Pygo1 was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios and increased cell size. The canonical β-catenin/T-cell transcription factor 4 complex was abundant in Pygo1-overexpressingtransgenic(Pygo1-TG) cardiac tissue,and the downstream genes of Wnt signaling, i.e., Axin2, Ephb3, and C-myc, were upregulated. A tail vein injection of β-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodelling in Pygo1-TG mice. Furthermore, in vivo downregulated pygo1 during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.

scholarly journals From blastocyst to gastrula: gene regulatory networks of embryonic stem cells and early mouse embryogenesis

2014 ◽  
Vol 369 (1657) ◽  
pp. 20130542 ◽  
Author(s):  
David-Emlyn Parfitt ◽  
Michael M. Shen
Keyword(s):  
Stem Cells ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Network Models ◽  
Cell Types ◽  
Mammalian Development ◽  
A Genome

To date, many regulatory genes and signalling events coordinating mammalian development from blastocyst to gastrulation stages have been identified by mutational analyses and reverse-genetic approaches, typically on a gene-by-gene basis. More recent studies have applied bioinformatic approaches to generate regulatory network models of gene interactions on a genome-wide scale. Such models have provided insights into the gene networks regulating pluripotency in embryonic and epiblast stem cells, as well as cell-lineage determination in vivo . Here, we review how regulatory networks constructed for different stem cell types relate to corresponding networks in vivo and provide insights into understanding the molecular regulation of the blastocyst–gastrula transition.

Abstract P189: RhoA Functions as an Antihypertrophic Switch in the Mouse Heart

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Davy Vanhoutte ◽  
Jop Van Berlo ◽  
Allen J York ◽  
Yi Zheng ◽  
Jeffery D Molkentin
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Small Gtpase ◽  
Mouse Heart ◽  
Activity Levels ◽  
Lung Weight ◽  
Pathological Cardiac Hypertrophy ◽  
Rhoa Protein

Background. Small GTPase RhoA has been previously implicated as an important signaling effector within the cardiomyocyte. However, recent studies have challenged the hypothesized role of RhoA as an effector of cardiac hypertrophy. Therefore, this study examined the in vivo role of RhoA in the development of pathological cardiac hypertrophy. Methods and results . Endogenous RhoA protein expression and activity levels (GTP-bound) in wild-type hearts were significantly increased after pressure overload induced by transverse aortic constriction (TAC). To investigate the necessity of RhoA within the adult heart, RhoA-LoxP-targeted (RhoA flx/flx ) mice were crossed with transgenic mice expressing Cre recombinase under the control of the endogenous cardiomyocyte-specific β-myosin heavy chain (β-MHC) promoter to generate RhoA βMHC-cre mice. Deletion of RhoA with β-MHC-Cre produced viable adults with > 85% loss of RhoA protein in the heart, without altering the basic architecture and function of the heart compared to control hearts, at both 2 and 8 months of age. However, subjecting RhoA βMHC-cre hearts to 2 weeks of TAC resulted in marked increase in cardiac hypertrophy (HW/BW (mg/g): 9.5 ± 0.3 for RhoA βMHC-cre versus 7.7 ± 0.4 for RhoA flx/flx ; and cardiomyocyte size (mm 2 ): 407 ± 21 for RhoA βMHC-cre versus 262 ± 8 for RhoA flx/flx ; n ≥ 8 per group; p<0.01) and a significantly increased fibrotic response. Moreover, RhoA βMHC-cre hearts transitioned more quickly into heart failure whereas control mice maintained proper cardiac function (fractional shortening (%): 23.3 ± 1.2 for RhoA βMHC-cre versus 29.3 ± 1.2 for RhoA flx/flx ; n ≥ 8 per group; p<0.01; 12 weeks after TAC). The latter was further associated with a significant increase in lung weight normalized to body weight and re-expression of the cardiac fetal gene program. In addition, these mice also displayed greater cardiac hypertrophy in response to 2 weeks of angiotensinII/phenylephrine infusion. Conclusion. These data identify RhoA as an antihypertrophic molecular switch in the mouse heart.

scholarly journals The Mechanism of High-Output Cardiac Hypertrophy Arising From Potassium Channel Gain-of-Function in Cantú Syndrome

Function ◽  
2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Conor McClenaghan ◽  
Yan Huang ◽  
Scot J Matkovich ◽  
Attila Kovacs ◽  
Carla J Weinheimer ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Potassium Channel ◽  
Cardiac Remodeling ◽  
Expression Patterns ◽  
Katp Channels ◽  
Gain Of Function ◽  
High Output Heart Failure ◽  
Altered Gene ◽  
Cardiac Enlargement ◽  
High Output

Abstract Dramatic cardiomegaly arising from gain-of-function (GoF) mutations in the ATP-sensitive potassium (KATP) channels genes, ABCC9 and KCNJ8, is a characteristic feature of Cantú syndrome (CS). How potassium channel over-activity results in cardiac hypertrophy, as well as the long-term consequences of cardiovascular remodeling in CS, is unknown. Using genome-edited mouse models of CS, we therefore sought to dissect the pathophysiological mechanisms linking KATP channel GoF to cardiac remodeling. We demonstrate that chronic reduction of systemic vascular resistance in CS is accompanied by elevated renin–angiotensin signaling, which drives cardiac enlargement and blood volume expansion. Cardiac enlargement in CS results in elevation of basal cardiac output, which is preserved in aging. However, the cardiac remodeling includes altered gene expression patterns that are associated with pathological hypertrophy and are accompanied by decreased exercise tolerance, suggestive of reduced cardiac reserve. Our results identify a high-output cardiac hypertrophy phenotype in CS which is etiologically and mechanistically distinct from other myocardial hypertrophies, and which exhibits key features of high-output heart failure (HOHF). We propose that CS is a genetically-defined HOHF disorder and that decreased vascular smooth muscle excitability is a novel mechanism for HOHF pathogenesis.

scholarly journals Muscle ring finger 1 mediates cardiac atrophy in vivo

2009 ◽  
Vol 296 (4) ◽  
pp. H997-H1006 ◽  
Author(s):  
Monte S. Willis ◽  
Mauricio Rojas ◽  
Luge Li ◽  
Craig H. Selzman ◽  
Ru-Hang Tang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Transcriptional Activation ◽  
Smooth Muscle Actin ◽  
Ring Finger ◽  
Left Ventricular ◽  
Cardiac Mass ◽  
Wild Type ◽  
Cardiac Atrophy ◽  
Pathological Cardiac Hypertrophy

Pathological cardiac hypertrophy, induced by various etiologies such as high blood pressure and aortic stenosis, develops in response to increased afterload and represents a common intermediary in the development of heart failure. Understandably then, the reversal of pathological cardiac hypertrophy is associated with a significant reduction in cardiovascular event risk and represents an important, yet underdeveloped, target of therapeutic research. Recently, we determined that muscle ring finger-1 (MuRF1), a muscle-specific protein, inhibits the development of experimentally induced pathological; cardiac hypertrophy. We now demonstrate that therapeutic cardiac atrophy induced in patients after left ventricular assist device placement is associated with an increase in cardiac MuRF1 expression. This prompted us to investigate the role of MuRF1 in two independent mouse models of cardiac atrophy: 1) cardiac hypertrophy regression after reversal of transaortic constriction (TAC) reversal and 2) dexamethasone-induced atrophy. Using echocardiographic, histological, and gene expression analyses, we found that upon TAC release, cardiac mass and cardiomyocyte cross-sectional areas in MuRF1−/− mice decreased ∼70% less than in wild type mice in the 4 wk after release. This was in striking contrast to wild-type mice, who returned to baseline cardiac mass and cardiomyocyte size within 4 days of TAC release. Despite these differences in atrophic remodeling, the transcriptional activation of cardiac hypertrophy measured by β-myosin heavy chain, smooth muscle actin, and brain natriuretic peptide was attenuated similarly in both MuRF1−/− and wild-type hearts after TAC release. In the second model, MuRF1−/− mice also displayed resistance to dexamethasone-induced cardiac atrophy, as determined by echocardiographic analysis. This study demonstrates, for the first time, that MuRF1 is essential for cardiac atrophy in vivo, both in the setting of therapeutic regression of cardiac hypertrophy and dexamethasone-induced atrophy.

scholarly journals Corrigendum: A Multi-Network Comparative Analysis of Transcriptome and Translatome Identifies Novel Hub Genes in Cardiac Remodeling

2021 ◽  
Vol 12 ◽  
Author(s):  
Etienne Boileau ◽  
Shirin Doroudgar ◽  
Eva Riechert ◽  
Lonny Jürgensen ◽  
Thanh Cao Ho ◽  
...  
Keyword(s):  
Comparative Analysis ◽  
Cardiac Remodeling ◽  
Hub Genes

scholarly journals Myricetin Alleviates Pathological Cardiac Hypertrophy via TRAF6/TAK1/MAPK and Nrf2 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Hai-han Liao ◽  
Nan Zhang ◽  
Yan-yan Meng ◽  
Hong Feng ◽  
Jing-jing Yang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Mapk Signaling ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Pathological Cardiac Hypertrophy ◽  
Pathological Hypertrophy ◽  
Nrf2 Signaling Pathway

Myricetin (Myr) is a common plant-derived polyphenol and is well recognized for its multiple activities including antioxidant, anti-inflammation, anticancer, and antidiabetes. Our previous studies indicated that Myr protected mouse heart from lipopolysaccharide and streptozocin-induced injuries. However, it remained to be unclear whether Myr could prevent mouse heart from pressure overload-induced pathological hypertrophy. Wild type (WT) and cardiac Nrf2 knockdown (Nrf2-KD) mice were subjected to aortic banding (AB) surgery and then administered with Myr (200 mg/kg/d) for 6 weeks. Myr significantly alleviated AB-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction in both WT and Nrf2-KD mice. Myr also inhibited phenylephrine- (PE-) induced neonatal rat cardiomyocyte (NRCM) hypertrophy and hypertrophic markers’ expression in vitro. Mechanically, Myr markedly increased Nrf2 activity, decreased NF-κB activity, and inhibited TAK1/p38/JNK1/2 MAPK signaling in WT mouse hearts. We further demonstrated that Myr could inhibit TAK1/p38/JNK1/2 signaling via inhibiting Traf6 ubiquitination and its interaction with TAK1 after Nrf2 knockdown in NRCM. These results strongly suggested that Myr could attenuate pressure overload-induced pathological hypertrophy in vivo and PE-induced NRCM hypertrophy via enhancing Nrf2 activity and inhibiting TAK1/P38/JNK1/2 phosphorylation by regulating Traf6 ubiquitination. Thus, Myr might be a potential strategy for therapy or adjuvant therapy for malignant cardiac hypertrophy.

scholarly journals NULP1 Alleviates Cardiac Hypertrophy by Suppressing NFAT3 Transcriptional Activity

2020 ◽  
Vol 9 (16) ◽  
Author(s):  
Xin Zhang ◽  
Fang Lei ◽  
Xiao‐Ming Wang ◽  
Ke‐Qiong Deng ◽  
Yan‐Xiao Ji ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Transcriptional Activity ◽  
Therapeutic Strategy ◽  
Aortic Banding ◽  
Activated T Cells ◽  
Rat Cardiomyocytes ◽  
Helix Loop Helix ◽  
Pathological Cardiac Hypertrophy ◽  
Transcription Activators

Background The development of pathological cardiac hypertrophy involves the coordination of a series of transcription activators and repressors, while their interplay to trigger pathological gene reprogramming remains unclear. NULP1 (nuclear localized protein 1) is a member of the basic helix‐loop‐helix family of transcription factors and its biological functions in pathological cardiac hypertrophy are barely understood. Methods and Results Immunoblot and immunostaining analyses showed that NULP1 expression was consistently reduced in the failing hearts of patients and hypertrophic mouse hearts and rat cardiomyocytes. Nulp1 knockout exacerbates aortic banding‐induced cardiac hypertrophy pathology, which was significantly blunted by transgenic overexpression of Nulp1 . Signal pathway screening revealed the nuclear factor of activated T cells (NFAT) pathway to be dramatically suppressed by NULP1. Coimmunoprecipitation showed that NULP1 directly interacted with the topologically associating domain of NFAT3 via its C‐terminal region, which was sufficient to suppress NFAT3 transcriptional activity. Inactivation of the NFAT pathway by VIVIT peptides in vivo rescued the aggravated pathogenesis of cardiac hypertrophy resulting from Nulp1 deficiency. Conclusions NULP1 is an endogenous suppressor of NFAT3 signaling under hypertrophic stress and thus negatively regulates the pathogenesis of cardiac hypertrophy. Targeting overactivated NFAT by NULP1 may be a novel therapeutic strategy for the treatment of pathological cardiac hypertrophy and heart failure.

Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo

2006 ◽  
Vol 291 (2) ◽  
pp. H600-H611 ◽  
Author(s):  
Anthony Azakie ◽  
Jeffrey R. Fineman ◽  
Youping He
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Troponin ◽  
Troponin T ◽  
Cardiac Troponin T ◽  
Pathological Cardiac Hypertrophy ◽  
Cardiac Gene Expression ◽  
Cardiac Gene ◽  
Embryonic Cardiomyocytes

Combinatorial interactions between cis elements and trans-acting factors are required for regulation of cardiac gene expression during normal cardiac development and pathological cardiac hypertrophy. Sp factors bind GC boxes and are implicated in recruitment and assembly of the basal transcriptional complex. In this study, we show that the cardiac troponin T (cTnT) promoter contains a GC box that is necessary for basal and cAMP-mediated activity of cTnT promoter constructs transfected in embryonic cardiomyocytes. Cardiac nuclear proteins bind the cTnT GC box in a sequence-specific fashion and consist of Sp1, Sp2, and Sp3 protein factors. By chromatin immunoprecipitation, Sp1 binds the cTnT promoter “in vivo.” Cotransfected Sp1 trans-activates the cTnT promoter in cardiomyocytes in culture. Sp3 represses Sp1-mediated transcriptional activation of the cTnT gene in embryonic cardiomyocytes. Sp3 repression of Sp1-mediated cTnT promoter activation is dose dependent, inferring a mechanism of competitive binding/inhibition. To evaluate the role of Sp factors in cardiac gene expression in vivo, we have established a clinically relevant animal model of pathological cardiac hypertrophy where the fetal cardiac program is activated. In this animal model, cardiac hypertrophy results from increased left-right shunting, volume loading of the left ventricle, and pressure loading of the right ventricle. Sp1 expression is increased in all four hypertrophied cardiac chambers, whereas Sp3 expression is diminished. This observation is consistent with the in vitro activating function of Sp1 and inhibitory effects of Sp3 on activity of cTnT promoter constructs. Sp factor levels are modulated during the hypertrophic cardiac program in vivo.

scholarly journals Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease

Science ◽  
2020 ◽  
pp. eabd0724
Author(s):  
Christina V. Theodoris ◽  
Ping Zhou ◽  
Lei Liu ◽  
Yu Zhang ◽  
Tomohiro Nishino ◽  
...  
Keyword(s):  
Machine Learning ◽  
Aortic Valve ◽  
Small Molecules ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Disease Model ◽  
Induced Pluripotent Stem Cell ◽  
Valve Disease ◽  
Heart Valve Disease

Mapping the gene regulatory networks dysregulated in human disease would allow the design of network-correcting therapies that treat the core disease mechanism. However, small molecules are traditionally screened for their effects on one to several outputs at most, biasing discovery and limiting the likelihood of true disease-modifying drug candidates. Here, we developed a machine learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell (iPSC) disease model of a common form of heart disease involving the aortic valve. Gene network correction by the most efficacious therapeutic candidate, XCT790, generalized to patient-derived primary aortic valve cells and was sufficient to prevent and treat aortic valve disease in vivo in a mouse model. This strategy, made feasible by human iPSC technology, network analysis, and machine learning, may represent an effective path for drug discovery.

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