Abstract P158: MicroRNA-22 Modulates Cardiac Gene Expression and Controls Compensation to Hemodynamic Stress in Mice

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Priyatansh Gurha ◽  
Robert Kelm ◽  
Mark Entman ◽  
George Taffet ◽  
Allan Bradley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Mouse Heart ◽  
Primary Role ◽  
Translational Repressor ◽  
Muscle Gene Expression ◽  
Hemodynamic Stress

Recent evidence suggests that miRNAs play an important role in cardiac morphogenesis and pathophyiology of heart failure. To explore the role of miR-22 in the mouse heart physiology, we generated miR-22 null (KO) mice. Although, miR-22 KO mice showed normal cardiac structure and function at baseline, these mice are sensitized to maladaptive remodeling (cardiac dilation) and decompensation in response to pressure overload by transverse aortic constrictions (TAC) stimulation. Genome-wide molecular analysis of KO hearts revealed attenuated expression of numerous CarG-dependent genes encoding proteins that reside at the sarcomeric Z-disc (including Myh7, Acta1, Mlp, Melusin, MyoZ2) indicating that miR-22 is required for optimum muscle gene expression. Alterations in sarcomeric gene expression is especially interesting as this suggests a primary role of miR-22 in controlling cardiac contractility and adaptation to stress. Targetomics analysis revealed that mechanistically this effect could be modulated in part by miR-22 target PURB (Purine Rich element binding protein B), a transcriptional/translational repressor. In conclusion we define a critical role of miR-22 in cardiac adaptation to hemodynamic stress. Furthermore, these data provides a previously unseen essential molecular mechanism that underlies homeostatic control of sarcomeric protein expression in the heart.

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

2004 ◽  
Vol 287 (5) ◽  
pp. H1957-H1966 ◽  
Author(s):  
Faina Schwartz ◽  
Arvi Duka ◽  
Irena Duka ◽  
Jing Cui ◽  
Haralambos Gavras
Keyword(s):  
Gene Expression ◽  
Cardiac Remodeling ◽  
Unknown Function ◽  
Mouse Heart ◽  
Ang Ii ◽  
Coordinate Regulation ◽  
Transcriptional Changes ◽  
Novel Targets ◽  
Molecular Circuitry

Although the central role of ANG II in cardiovascular homeostasis is well appreciated, the molecular circuitry of its many actions is not completely understood. With the use of serial analysis of gene expression to assess global transcriptional changes in the heart of mice after continuous 7-day ANG II administration, we identified patterns of gene expression indicative of cardiac remodeling, including coordinate regulation of genes previously described in a context of processes associated with hypertrophy and fibrosis. In addition, we discovered several novel ANG II targets, including characterized genes of known function, recently annotated genes of unknown function, and the putative genes not yet present in current databases. The serial analysis of gene expression approach to assess the role of ANG II presented in this report provides new venues for inquiries into ANG II-mediated cardiac function.

Abstract P317: Cardiac Fibroblast GSK3α Promotes Myocardial Fibrotic Remodeling Through GSK3α-ERK-IL11 Signaling Circuit

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Prachi Umbarkar ◽  
Sultan Tousif ◽  
Anand P Singh ◽  
Joshua C Anderson ◽  
qinkun zhang ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Collagen Gel ◽  
Pressure Overload ◽  
Negative Regulator ◽  
Post Injury

Background: Myocardial fibrosis contributes significantly to heart failure (HF). Fibroblasts are among the predominant cell type in the heart and are primary drivers of fibrosis. To identify the kinases involved in fibrosis, we analyzed the kinome of mouse cardiac fibroblasts (CF) isolated from normal and failing hearts. This unbiased screening revealed the critical role of the GSK-3 family-centric pathways in fibrosis. Previously we have shown that among two isoforms of GSK3, CF-GSK3β acts as a negative regulator of fibrosis in the injured heart. However, the role of CF-GSK3α in the pathogenesis of cardiac diseases is completely unknown. Methods and Results: To define the role of CF-GSK3α in HF, we employed two novel fibroblast-specific KO mouse models. Specifically, GSK3α was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or periostin- promoter-driven Cre recombinase. In both models, GSK3α deletion restricted pressure overload-induced cardiac fibrosis and preserved cardiac function. We examined the effect of GSK3α deletion on myofibroblast transformation and pro-fibrotic TGFβ1-SMAD3 signaling in vitro . A significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGFβ1-treated KO CFs confirmed that GSK3α is required for myofibroblast transformation. Surprisingly, GSK3α deletion did not affect SMAD3 activation, indicating the pro-fibrotic role of GSK3α is SMAD3 independent. To further delineate the underlying mechanisms, proteins were isolated from CFs of WT and KO mice at 4 weeks post-injury, and kinome profiling was performed. The kinome analysis identified the downregulation of RAF family kinase activity in KO CFs. Moreover, mapping of significantly altered kinases against literature annotated interactions generated ERK-centric networks. Consistently, flow cytometric analysis of CFs confirmed significantly low levels of pERK in KO mice. Additionally, our in vitro studies demonstrated that GSK3α deletion prevents TGFβ1-induced ERK activation. Interestingly, IL-11, a pro-fibrotic downstream effector of TGFβ1, was remarkably reduced in KO CFs and ERK inhibition further decreased IL-11 expression. Taken together, herein, we discovered the GSK3α-ERK-IL-11 signaling as a critical pro-fibrotic pathway in the heart. Strategies to inhibit this pro-fibrotic network could prevent adverse fibrosis and HF. Conclusion: CF-GSK3α plays a causal role in myocardial fibrosis that could be therapeutically targeted for future clinical applications.

Abstract 791: A Critical Role for Bmper (BMP-binding Endothelial cell precursor-derived Regulator) in Cardiac Muscle Mass Regulation during Development and Pressure Overload Induced Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Monte Willis ◽  
Rongqin Ren ◽  
Cam Patterson
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Muscle Mass ◽  
Cardiac Development ◽  
Critical Role ◽  
Pressure Overload ◽  
Posterior Wall ◽  
Fractional Shortening

Bone morphogenetic proteins (BMPs) of the TGF-beta superfamily, have been implicated in multiple processes during cardiac development. Our laboratory recently described an unprecedented role for Bmper in antagonizing BMP-2, BMP-4, and BMP-6. To determine the role of Bmper on cardiac development in vivo, we created Bmper null (Bmper −/−) mice by replacing exons 1 and 2 with GFP. Since Bmper −/− mice are perinatally lethal, we determined pre-natal cardiac function of Bmper −/− mice in utero just before birth. By echocardiography, E18.5 Bmper −/− embryos had decreased cardiac function (24.2 +/− 8.1% fractional shortening) compared to Bmper +/− and Bmper +/+ siblings (52.2 +/− 1.6% fractional shortening) (N=4/group). To further characterize the role of Bmper on cardiac function in adult mice, we performed echocardiography on 8-week old male and female Bmper +/− and littermate control Bmper +/+. Bmper +/− mice had an approximately 15% decrease in anterior and posterior wall thickness compared to sibling Bmper +/+ mice at baseline (n=10/group). Cross-sectional areas of Bmper +/− cardiomyocytes were approximately 20% less than wild type controls, indicating cardiomyocyte hypoplasia in adult Bmper +/− mice at baseline. Histologically, no significant differences were identified in representative H&E and trichrome stained adult Bmper +/− and Bmper +/+ cardiac sections at baseline. To determine the effects of Bmper expression on the development of cardiac hypertrophy, both Bmper +/− and Bmper +/+ sibling controls underwent transaortic constriction (TAC), followed by weekly echocardiography. While a deficit was identified in Bmper +/− mice at baseline, both anterior and posterior wall thicknesses increased after TAC, such that identical wall thicknesses were identified in Bmper +/− and Bmper +/+ mice 1–4 weeks after TAC. Notably, cardiac function (fractional shortening %) and histological evaluation revealed no differences between Bmper +/− and Bmper +/+ any time after TAC. These studies identify for the first time that Bmper expression plays a critical role in regulating cardiac muscle mass during development, and that Bmper regulates the development of hypertrophy in response to pressure overload in vivo.

A critical role of Sp1 transcription factor in regulating gene expression in response to insulin and other hormones

Life Sciences ◽  
2008 ◽  
Vol 83 (9-10) ◽  
pp. 305-312 ◽  
Author(s):  
Solomon S. Solomon ◽  
Gipsy Majumdar ◽  
Antonio Martinez-Hernandez ◽  
Rajendra Raghow
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Critical Role ◽  
Sp1 Transcription Factor

An analysis of culmination in Dictyostelium using prestalk and stalk-specific cell autonomous markers

Development ◽  
1991 ◽  
Vol 111 (3) ◽  
pp. 779-787 ◽  
Author(s):  
K.A. Jermyn ◽  
J.G. Williams
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Dictyostelium Discoideum ◽  
Tube Formation ◽  
Matrix Proteins ◽  
Specific Cell ◽  
Primary Role ◽  
Fusion Genes ◽  
Spore Mass

The ecmA (pDd63) and ecmB (pDd56) genes encode extracellular matrix proteins of the slime sheath and stalk tube of Dictyostelium discoideum. Using fusion genes containing the promoter of one or other gene coupled to an immunologically detectable reporter, we previously identified two classes of prestalk cells in the tip of the migrating slug; a central core of pstB cells, which express the ecmB gene, surrounded by pstA cells, which express the ecmA gene. PstB cells lie at the position where stalk tube formation is initiated at culmination and we show that they act as its founders. As culmination proceeds, pstA cells transform into pstB cells by activating the ecmB gene as they enter the stalk tube. The prespore region of the slug contains a population of cells, termed anterior-like cells (ALC), which have the characteristics of prestalk cells. We show that the ecmA and ecmB genes are expressed at a low level in ALC during slug migration and that their expression in these cells is greatly elevated during culmination. Previous observations have shown that ALC sort to surround the prespore cells during culmination (Sternfeld and David, 1982 Devl Biol. 93, 111–118) and we find just such a distribution for pstB cells. We believe that the ecmB protein plays a structural role in the stalk tube and its presence, as a cradle around the spore head, suggests that it may play a further function, perhaps in ensuring integrity of the spore mass during elevation. If this interpretation is correct, then a primary role of anterior-like cells may be to form these structures at culmination. We previously identified a third class of prestalk cells, pstO cells, which lie behind pstA cells in the slug anterior and which appeared to express neither the ecmA nor the ecmB gene. Using B-galactosidase fusion constructs, which give more sensitive detection of gene expression, we now find that these cells express the ecmA gene but at a much lower level than pstA cells. We also show that expression of the ecmA gene becomes uniformly high throughout the prestalk zone when slugs are allowed to migrate in the light. Overhead light favours culmination and it may be that increased expression of the ecmA gene in the pst ‘O’ region is a preparatory step in the process.

Abstract 238: Loss of AKAP150 Promotes Pathological Remodeling and Heart Failure Propensity by Disrupting Calcium Homeostasis and Contractile Reserve

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Lei Li ◽  
Jing Li ◽  
Benjamin Drum ◽  
Yi Chen ◽  
Haifeng Yin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Critical Role ◽  
Pressure Overload ◽  
Contractile Reserve ◽  
Mouse Heart ◽  
Adrenergic Stimulation ◽  
Anchoring Protein ◽  
Key Aspects ◽  
Myocyte Contractility ◽  
Pathological Remodeling

Impaired Ca 2+ cycling and myocyte contractility are a hallmark of heart failure triggered by pathological stress such as hemodynamic overload. The A-Kinase anchoring protein AKAP150 has been shown to coordinate key aspects of adrenergic regulation of Ca 2+ cycling and excitation-contraction in cardiomyocytes. However, the role of the AKAP150 signaling complexes in the pathogenesis of heart failure is largely unknown. Here we investigate how AKAP150 signaling complexes impact Ca 2+ cycling, myocyte contractility, and heart failure susceptibility following pathological stress. We detected a significant reduction of AKAP150 expression in the failing mouse heart induced by pressure overload. Importantly, cardiac-specific AKAP150 knockout mice were predisposed to develop dilated cardiomyopathy with severe cardiac dysfunction and fibrosis after pressure overload. Loss of AKAP150 also promoted pathological remodeling and heart failure progression following myocardial infarction. However, ablation of AKAP150 did not appear to affect chronic activation of calcineurin-NFAT signaling in cardiomyocytes or pressure overload- or agonist- induced cardiac hypertrophy. Immunoprecipitation studies showed that AKAP150 was associated with SERCA2, phospholamban, and ryanodine receptor-2, providing a targeted control of sarcoplasmic reticulum Ca 2+ regulatory proteins. Mechanistically, loss of AKAP150 led to impaired Ca 2+ cycling and reduced myocyte contractility reserve following adrenergic stimulation or pressure overload. These findings define a critical role for AKAP150 in maintaining Ca 2+ homeostasis and myocardial ionotropy following pathological stress, suggesting the AKAP150 signaling pathway may serve as a novel therapeutic target for heart failure.

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 β1-Integrin and PI 3-kinase regulate RhoA-dependent activation of skeletal α-actin promoter in myoblasts

2000 ◽  
Vol 278 (6) ◽  
pp. H1736-H1743 ◽  
Author(s):  
Lei Wei ◽  
Wei Zhou ◽  
Lu Wang ◽  
Robert J. Schwartz
Keyword(s):  
Gene Expression ◽  
Promoter Activity ◽  
Serum Response Factor ◽  
Critical Role ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Muscle Gene Expression ◽  
Actin Promoter ◽  
Muscle Gene ◽  
Negative Mutant

RhoA GTPase, a regulator of actin cytoskeleton, is also involved in regulating c- fos gene expression through its effect on serum response factor (SRF) transcriptional activity. We have also shown that RhoA plays a critical role in myogenesis and regulates expression of SRF-dependent muscle genes, including skeletal α-actin. In the present study, we examined whether the RhoA signaling pathway cross talks with other myogenic signaling pathways to modulate skeletal α-actin promoter activity in myoblasts. We found that extracellular matrix proteins and the β1-integrin stimulated RhoA-dependent activation of the α-actin promoter. The muscle-specific isoform β1Dselectively activated the α-actin promoter in concert with RhoA but inhibited the c- fos promoter. In addition, focal adhesion kinase (FAK) and phosphatidylinositol (PI) 3-kinase were required for full activation of the α-actin promoter by RhoA. Expression of a dominant negative mutant of FAK, application of wortmannin to cultured myoblasts, or expression of a dominant negative mutant of PI 3-kinase inhibited α-actin promoter activity induced by RhoA. These results suggest that RhoA, β1-integrin, FAK, and PI 3-kinase serve together as an important signaling network in regulating muscle gene expression.

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