Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene

2001 ◽  
Vol 280 (1) ◽  
pp. H151-H159 ◽  
Author(s):  
Kalev Freeman ◽  
Cynthia Colon-Rivera ◽  
M. Charlotte Olsson ◽  
Russell L. Moore ◽  
Howard D. Weinberger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dilated Cardiomyopathy ◽  
Exercise Tolerance ◽  
Heart Function ◽  
Isolated Heart ◽  
Transgenic Animals ◽  
Actin Binding ◽  
Isolated Hearts ◽  
Cardiac Decompensation

A mouse model of hypertrophic cardiomyopathy (HCM) was created by expression of a cardiac α-myosin transgene including the R403Q mutation and a deletion of a segment of the actin-binding domain. HCM mice show early histopathology and hypertrophy, with progressive hypertrophy in females and ventricular dilation in older males. To test the hypothesis that dilated cardiomyopathy (DCM) is part of the pathological spectrum of HCM, we studied chamber morphology, exercise tolerance, hemodynamics, isolated heart function, adrenergic sensitivity, and embryonic gene expression in 8- to 11-mo-old male transgenic animals. Significantly impaired exercise tolerance and both systolic and diastolic dysfunction were seen in vivo. Contraction and relaxation parameters of isolated hearts were also decreased, and lusitropic responsiveness to the β-adrenergic agonist isoproterenol was modestly reduced. Myocardial levels of the G protein-coupled β-adrenergic receptor kinase 1 (β-ARK1) were increased by more than twofold over controls, and total β-ARK1 activity was also significantly elevated. Induction of fetal gene expression was also observed in transgenic hearts. We conclude that transgenic male animals have undergone cardiac decompensation resulting in a DCM phenotype. This supports the idea that HCM and DCM may be part of a pathological continuum rather than independent diseases.

Serial analysis of gene expression (SAGE) during porcine embryo development

2004 ◽  
Vol 16 (2) ◽  
pp. 87 ◽  
Author(s):  
Le Ann Blomberg ◽  
Kurt A. Zuelke
Keyword(s):  
Gene Expression ◽  
Functional Genomics ◽  
Embryo Development ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Transgenic Animals ◽  
Specific Gene ◽  
Research Strategies

Functional genomics provides a powerful means for delving into the molecular mechanisms involved in pre-implantation development of porcine embryos. High rates of embryonic mortality (30%), following either natural mating or artificial insemination, emphasise the need to improve the efficiency of reproduction in the pig. The poor success rate of live offspring from in vitro-manipulated pig embryos also hampers efforts to generate transgenic animals for biotechnology applications. Previous analysis of differential gene expression has demonstrated stage-specific gene expression for in vivo-derived embryos and altered gene expression for in vitro-derived embryos. However, the methods used to date examine relatively few genes simultaneously and, thus, provide an incomplete glimpse of the physiological role of these genes during embryogenesis. The present review will focus on two aspects of applying functional genomics research strategies for analysing the expression of genes during elongation of pig embryos between gestational day (D) 11 and D12. First, we compare and contrast current methodologies that are being used for gene discovery and expression analysis during pig embryo development. Second, we establish a paradigm for applying serial analysis of gene expression as a functional genomics tool to obtain preliminary information essential for discovering the physiological mechanisms by which distinct embryonic phenotypes are derived.

scholarly journals Crustacean cardioexcitatory peptides may inhibit the heart in vivo.

1995 ◽  
Vol 198 (12) ◽  
pp. 2547-2550 ◽  
Author(s):  
I J McGaw ◽  
J L Wilkens ◽  
B R McMahon ◽  
C N Airriess
Keyword(s):  
Stroke Volume ◽  
Isolated Heart ◽  
Cancer Magister ◽  
Isolated Hearts ◽  
Cardiovascular Performance ◽  
Cast Doubt ◽  
Cardiac Stroke Volume

Peptide neurohormones exist as functionally similar analogues in a wide variety of invertebrate and vertebrate phyla, and many have been implicated as cardiovascular regulators. In decapod crustaceans, these include the pentapeptide proctolin, crustacean cardioactive peptide (CCAP) and the FMRF amide-related peptides F1 and F2, all of which are found in the pericardial organs located immediately upstream of the heart. Cardioexcitatory activity has been demonstrated by these four peptides in both isolated and semi-isolated arthropod hearts; CCAP, however, has minimal effects on the heart of Cancer magister. In the present study, we determined the effects of proctolin, F1 and F2 on the heart of the crab C. magister in both in vitro (semi-isolated heart) and in vivo (whole animal) preparations. In semi-isolated hearts, infusion of each peptide caused cardioexcitation, increasing the rate and stroke volume of the heart. In whole crabs, the peptides were cardioinhibitory; the strongest effects were observed with F1 and F2, which dramatically decreased heart rate, cardiac stroke volume and cardiac output. These results cast doubt on current perceptions of the functional role of cardioactive peptides in the regulation of invertebrate cardiovascular performance in vivo.

Abstract 5290: Cypher Long but not Short Isoform Specific Knockout Mice Result in Cardiac Signaling Defects and Dilated Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hongqiang Cheng ◽  
Ming Zheng ◽  
Farah Sheikh ◽  
Kunfu Ouyang ◽  
Li Cui ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Gene Mutations ◽  
Splice Isoforms ◽  
Functional Roles ◽  
Deficient Mice

Our previous studies have demonstrated that Cypher, a PDZ-LIM protein localized at the Z line, plays a pivotal role in heart function. We recently identified long and short splice isoforms of Cypher, which are characterized by the presence and absence of LIM domains, respectively. The LIM domain of Cypher is thought to be involved in signaling, based on its ability to directly interact with signaling proteins. In human patients with dilated cardiomyopathy (DCM) we discovered Cypher gene mutations, which affect either long or short isoform or both isoforms. However, the precise molecular mechanisms underlying the role of Cypher isoforms in DCM remain unclear. To determine the role of Cypher isoforms in cardiac signaling and disease in vivo , we generated two Cypher isoform specific knockout mice. Selective ablation of Cypher long isoforms in mice resulted in partial neonatal lethality. However, hearts from viable Cypher long isoform deficient mice displayed Z line abnormalities and decreased cardiomyocyte widths, which resulted in a progressive form of DCM, characterized by fibrosis, calcification and lethality. The effects on cardiac function and disease observed in long-isoform specific Cypher knockout mice were preceded by significant decreases in cardiac protein kinase C and extracellular signal-regulated kinase signaling. These results are in contrast to Cypher short isoform deficient mice, which were viable with no overt cardiac morphology and signaling abnormalities. These results reveal distinct functional roles for Cypher isoforms in the heart as well as shed light into the molecular mechanisms underlying dilated cardiomyopathy.

Effects of in vivo and in vitro treatment with L-carnitine on isolated hearts from chronically diabetic rats

1990 ◽  
Vol 68 (8) ◽  
pp. 1085-1092 ◽  
Author(s):  
Brian Rodrigues ◽  
John R. Ross ◽  
Sepehr Farahbakshian ◽  
John H. McNeill
Keyword(s):  
Heart Function ◽  
Protective Action ◽  
Myocardial Damage ◽  
Diabetic Rats ◽  
Lipid Lowering ◽  
Pharmacological Effects ◽  
Isolated Hearts ◽  
In Vitro Treatment

The effects of in vivo and in vitro L-carnitine administration on cardiac function were studied in isolated perfused working hearts from control and diabetic rats. Injection of L-carnitine (3 g∙g−1∙day−1,i. p.) for 2 weeks into rats previously diabetic for 6 weeks partially reversed the adverse effects of chronic diabetes on heart function. In a second experiment, a lower dose of L-carnitine (0.5 g∙kg−1∙day−1,i.p.) injected for 6 weeks prevented the onset of heart dysfunction in chronically diabetic rats. The protective action of L-carnitine in the myocardium appeared to be independent of any direct pharmacological effects. In both studies, L-carnitine was a potent lipid-lowering agent. The data suggests that L-carnitine administration at either dose had a protective effect against myocardial damage seen during diabetes. The mechanism(s) underlying these effects remains to be elucidated but are discussed.Key words: diabetes, heart, cardiomyopathy, carnitine, lipids.

scholarly journals Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality

2015 ◽  
Vol 112 (44) ◽  
pp. 13573-13578 ◽  
Author(s):  
Christopher T. Pappas ◽  
Rachel M. Mayfield ◽  
Christine Henderson ◽  
Nima Jamilpour ◽  
Cathleen Cover ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Thin Filament ◽  
Striated Muscle ◽  
Heart Function ◽  
Contractile Force ◽  
Actin Binding ◽  
Actin Assembly ◽  
Thin Filaments ◽  
Filament Assembly ◽  
Muscle Thin Filament

Leiomodin 2 (Lmod2) is an actin-binding protein that has been implicated in the regulation of striated muscle thin filament assembly; its physiological function has yet to be studied. We found that knockout of Lmod2 in mice results in abnormally short thin filaments in the heart. We also discovered that Lmod2 functions to elongate thin filaments by promoting actin assembly and dynamics at thin filament pointed ends. Lmod2-KO mice die as juveniles with hearts displaying contractile dysfunction and ventricular chamber enlargement consistent with dilated cardiomyopathy. Lmod2-null cardiomyocytes produce less contractile force than wild type when plated on micropillar arrays. Introduction of GFP-Lmod2 via adeno-associated viral transduction elongates thin filaments and rescues structural and functional defects observed in Lmod2-KO mice, extending their lifespan to adulthood. Thus, to our knowledge, Lmod2 is the first identified mammalian protein that functions to elongate actin filaments in the heart; it is essential for cardiac thin filaments to reach a mature length and is required for efficient contractile force and proper heart function during development.

scholarly journals Identification and In Vivo Characterisation of Cardioactive Peptides in Drosophila melanogaster

2018 ◽  
Vol 20 (1) ◽  
pp. 2 ◽  
Author(s):  
Ronja Schiemann ◽  
Kay Lammers ◽  
Maren Janz ◽  
Jana Lohmann ◽  
Achim Paululat ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Heart Function ◽  
Transgenic Animals ◽  
Peptide Hormones ◽  
Biological Processes ◽  
Functional Conservation ◽  
Regulatory Systems ◽  
Evolutionarily Conserved ◽  
Diastolic Interval

Neuropeptides and peptide hormones serve as critical regulators of numerous biological processes, including development, growth, reproduction, physiology, and behaviour. In mammals, peptidergic regulatory systems are complex and often involve multiple peptides that act at different levels and relay to different receptors. To improve the mechanistic understanding of such complex systems, invertebrate models in which evolutionarily conserved peptides and receptors regulate similar biological processes but in a less complex manner have emerged as highly valuable. Drosophila melanogaster represents a favoured model for the characterisation of novel peptidergic signalling events and for evaluating the relevance of those events in vivo. In the present study, we analysed a set of neuropeptides and peptide hormones for their ability to modulate cardiac function in semi-intact larval Drosophila melanogaster. We identified numerous peptides that significantly affected heart parameters such as heart rate, systolic and diastolic interval, rhythmicity, and contractility. Thus, peptidergic regulation of the Drosophila heart is not restricted to chronotropic adaptation but also includes inotropic modulation. By specifically interfering with the expression of corresponding peptides in transgenic animals, we assessed the in vivo relevance of the respective peptidergic regulation. Based on the functional conservation of certain peptides throughout the animal kingdom, the identified cardiomodulatory activities may be relevant not only to proper heart function in Drosophila, but also to corresponding processes in vertebrates, including humans.

scholarly journals Overexpression of DAZL, STRA8, and BOULE Genes and Treatment With BMP4 or Retinoic Acid Modulate the Expression of MSC Overexpressing Germ Cell Genes

2021 ◽  
Vol 8 ◽  
Author(s):  
Paloma Cordero ◽  
Alejandra Guerrero-Moncayo ◽  
Monica De los Reyes ◽  
Manuel Varas-Godoy ◽  
Jahaira Cortez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Retinoic Acid ◽  
Germ Cell ◽  
Transgenic Animals ◽  
Mrna Levels ◽  
Adult Testis ◽  
Specific Distribution

In vitro gamete derivation from stem cells has potential applications in animal reproduction as an alternative method for the dissemination of elite animal genetics, production of transgenic animals, and conservation of endangered species. Mesenchymal stem cells (MSCs) may be suitable candidates for in vitro gamete derivation considering their differentiative capacity and their potential for cell therapy. Due to its relevance in gametogenesis, it has been reported that retinoic acid (RA) and bone morphogenetic protein (BMP) 4 are able to upregulate the expression of specific markers associated to the early stages of germ cell (GCs) differentiation in bovine fetal MSCs (bfMSCs). In the present study, we used polycistronic vectors containing combinations of GC genes DAZL, STRA8, and BOULE followed by exposure to BMP4 or RA to induce GC differentiation of bovine fetal adipose tissue-derived MSC (AT-MSCs). Cells samples at Day 14 were analyzed according to the expression of pluripotent genes NANOG and OCT4 and GC genes DAZL, STRA8, BOULE, PIWI, c-KIT, and FRAGILIS using Q-PCR. Fetal and adult testis and AT-MSCs samples were also analyzed for the expression of DAZL, STRA8, and NANOG using immunofluorescence. Increased gene expression levels in the adult testis and cell-specific distribution of DAZL, STRA8, and NANOG in the fetal testis suggest that these markers are important components of the regulatory network that control the in vivo differentiation of bovine GCs. Overexpression of DAZL and STRA8 in bi-cistronic and DAZL, STRA8, and BOULE in tri-cistronic vectors resulted in the upregulation of OCT4, NANOG, and PIWIL2 in bovine fetal AT-MSCs. While BMP4 repressed NANOG expression, this treatment increased DAZL and c-KIT and activated FRAGILIS expression in bovine fetal AT-MSCs. Treatment with RA for 14 days increased the expression of DAZL and FRAGILIS and maintained the mRNA levels of STRA8 in bovine fetal AT-MSCs transfected with bi-cistronic and tri-cistronic vectors. Moreover, RA treatment repressed the expression of OCT4 and NANOG in these cells. Thus, overexpression of DAZL, STRA8, and BOULE induced the upregulation of the pluripotent markers and PIWIL2 in transfected bovine fetal AT-MSCs. The partial activation of GC gene expression by BMP4 and RA suggests that both factors possess common targets but induce different gene expression effects during GC differentiation in overexpressing bovine fetal AT-MSCs.

scholarly journals Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming

2017 ◽  
Vol 312 (4) ◽  
pp. H768-H780 ◽  
Author(s):  
Kathryn M. Spitler ◽  
Jessica M. Ponce ◽  
Gavin Y. Oudit ◽  
Duane D. Hall ◽  
Chad E. Grueter
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cardiac Function ◽  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Heart Function ◽  
Expression Patterns ◽  
Left Ventricular ◽  
Sequencing Analysis ◽  
Early Lethality

The mediator complex, a multisubunit nuclear complex, plays an integral role in regulating gene expression by acting as a bridge between transcription factors and RNA polymerase II. Genetic deletion of mediator subunit 1 (Med1) results in embryonic lethality, due in large part to impaired cardiac development. We first established that Med1 is dynamically expressed in cardiac development and disease, with marked upregulation of Med1 in both human and murine failing hearts. To determine if Med1 deficiency protects against cardiac stress, we generated two cardiac-specific Med1 knockout mouse models in which Med1 is conditionally deleted (Med1cKO mice) or inducibly deleted in adult mice (Med1cKO-MCM mice). In both models, cardiac deletion of Med1 resulted in early lethality accompanied by pronounced changes in cardiac function, including left ventricular dilation, decreased ejection fraction, and pathological structural remodeling. We next defined how Med1 deficiency alters the cardiac transcriptional profile using RNA-sequencing analysis. Med1cKO mice demonstrated significant dysregulation of genes related to cardiac metabolism, in particular genes that are coordinated by the transcription factors Pgc1α, Pparα, and Errα. Consistent with the roles of these transcription factors in regulation of mitochondrial genes, we observed significant alterations in mitochondrial size, mitochondrial gene expression, complex activity, and electron transport chain expression under Med1 deficiency. Taken together, these data identify Med1 as an important regulator of vital cardiac gene expression and maintenance of normal heart function. NEW & NOTEWORTHY Disruption of transcriptional gene expression is a hallmark of dilated cardiomyopathy; however, its etiology is not well understood. Cardiac-specific deletion of the transcriptional coactivator mediator subunit 1 (Med1) results in dilated cardiomyopathy, decreased cardiac function, and lethality. Med1 deletion disrupted cardiac mitochondrial and metabolic gene expression patterns.

Abstract 471: Paradigm Shift to Epigenetic Memory for the Pathological Understanding of Chronic Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yoshihiro Asano ◽  
Seiji Takashima ◽  
Yulin Liao ◽  
Masafumi Kitakaze
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Transcription Factors ◽  
Chronic Heart Failure ◽  
Chromatin Structure ◽  
Epigenetic Modification ◽  
Heart Function ◽  
Epigenetic Mechanism ◽  
Epigenetic Markers

Background- Epigenetic modification becomes a popular regulatory mechanism of gene expression in development or tumor progression. However its role in cardiovascular diseases has not been elucidated. Since reactivation of cardiac fetal gene expression in chronic heart failure (CHF) is more remarkable than that expected by the increased transcriptional factors, the concept of epigenetic modification may be required for the explanation of such a phenomenon. We tested this idea. Methods- To test the epigenetic potency in cardiomyocytes, we focused on the expression of both BNP and ANP genes. As epigenetic markers, nucleic chromatin structure by electron microscopy and the entire-regional histone modifications were evaluated using our newly developed in vivo chromatin immunoprecipitation (ChIP) assay. Results- In the developmental stage of hearts, we observed a parallel movement of fetal gene expression and epigenetic markers. On the other hand, in the short time stimuli of GPCR agonists in murine cardiomyocytes, fetal gene expression was controlled only by the amount of transcription factors, Gata4 and Nkx2.5, but epigenetic maker was not altered. In contrast, in in vivo murine model of CHF both Gata4 and Nkx2.5 depressed despite elevated expression of both BNP and ANP. Nucleic chromatin structure in failing cardiomyocytes was changed to less condensed forms and increased accumulation of both histone H3K9-acetylation and H3K4-trimethylation was observed across these gene loci. Also in human failing heart, similar changes of nucleic chromatin structure were observed as that in murine CHF model and interestingly these changes was reversed when the heart function was recovered along with proper treatment. Conclusions- We for the first time clarified that both BNP and ANP reactivation mechanisms in chronic heart failure link to the alteration of histone modification by the in vivo ChIP method. Different from acute stimuli, this change was coincided with nucleic chromatin structure and was explicable of paradoxical depression of transcription factors, suggesting epigenetic potency. Epigenetic mechanism may play a pivotal role in the nuclear memory-mediating failing myocardium, raising the hope for a novel pathological understanding for human CHF.

scholarly journals NADH changes during hypoxia, ischemia, and increased work differ between isolated heart preparations

2014 ◽  
Vol 306 (4) ◽  
pp. H529-H537 ◽  
Author(s):  
Anastasia M. Wengrowski ◽  
Sarah Kuzmiak-Glancy ◽  
Rafael Jaimes ◽  
Matthew W. Kay
Keyword(s):  
Energy Supply ◽  
Oxygen Supply ◽  
Heart Function ◽  
Isolated Heart ◽  
Supply And Demand ◽  
Half Maximum ◽  
Low Oxygen ◽  
Heart Preparation ◽  
Perfused Hearts

Langendorff-perfused hearts and working hearts are established isolated heart preparation techniques that are advantageous for studying cardiac physiology and function, especially when fluorescence imaging is a key component. However, oxygen and energy requirements vary widely between isolated heart preparations. When energy supply and demand are not in harmony, such as when oxygen is not adequately available, the imbalance is reflected in NADH fluctuations. As such, NADH imaging can provide insight into the metabolic state of tissue. Hearts from New Zealand white rabbits were prepared as mechanically silenced Langendorff-perfused hearts, Langendorff-perfused hearts, or biventricular working hearts and subjected to sudden changes in workload, instantaneous global ischemia, and gradual hypoxia while heart rate, aortic pressure, and epicardial NADH fluorescence were monitored. Fast pacing resulted in a dip in NADH upon initiation and a spike in NADH when pacing was terminated in biventricular working hearts only, with the magnitude of the changes greatest at the fastest pacing rate. Working hearts were also most susceptible to changes in oxygen supply; NADH was at half-maximum value when perfusate oxygen was at 67.8 ± 13.7%. Langendorff-perfused and mechanically arrested hearts were the least affected by low oxygen supply, with half-maximum NADH occurring at 42.5 ± 5.0% and 23.7 ± 4.6% perfusate oxygen, respectively. Although the biventricular working heart preparation can provide a useful representation of mechanical in vivo heart function, it is not without limitations. Understanding the limitations of isolated heart preparations is crucial when studying cardiac function in the context of energy supply and demand.

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