scholarly journals The genetic basis of cardiac function: dissection by zebrafish ( Danio rerio ) screens

2000 ◽  
Vol 355 (1399) ◽  
pp. 939-944 ◽  
Author(s):  
Kerri S. Warren ◽  
Justina C. Wu ◽  
Florence Pinet ◽  
Mark C. Fishman
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Danio Rerio ◽  
Heart Diseases ◽  
Single Gene ◽  
Cardiac Contractility ◽  
Gene Mutations ◽  
Genetic Screens ◽  
Endothelial Lining ◽  
Normal Cardiac Function

The vertebrate heart differs from chordate ancestors both structurally and functionally. Genetic units of form, termed ‘modules’, are identifiable by mutation, both in zebrafish and mouse, and correspond to features recently acquired in evolution, such as the ventricular chamber or endothelial lining of the vessels and heart. Zebrafish ( Danio rerio ) genetic screens have provided a reasonably inclusive set of such genes. Normal cardiac function may also be disrupted by single–gene mutations in zebrafish. Individual mutations may perturb contractility or rhythm generation. The zebrafish mutations which principally disturb cardiac contractility fall into two broad phenotypic categories, ‘dilated’ and ‘hypertrophic’. Interestingly, these correspond to the two primary types of heart failure in humans. These disorders of early cardiac function provide candidate genes to be examined in complex human heart diseases, including arrhythmias and heart failure.

Abstract 360: MiR-133 Modulates the Beta1-Adrenergic Receptor Transduction Cascade

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Alessandra Castaldi ◽  
Tania Zaglia ◽  
Vittoria Di Mauro ◽  
Pierluigi Carullo ◽  
Giacomo Viggiani ◽  
...  
Keyword(s):  
Heart Failure ◽  
Nervous System ◽  
Sympathetic Nervous System ◽  
Cardiac Function ◽  
Cardiac Contractility ◽  
Experimental Studies ◽  
Mrna Translation ◽  
Loss Of Function ◽  
Sympathetic Nervous

Rationale: The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, over-activation of the sympathetic nervous system induces the release of catecholamines, which activate β-adrenergic receptors (βARs) in cardiomyocytes (CMs) and lead to increased heart rate and cardiac contractility. However, chronic stimulation of βARs leads to impaired cardiac function and β-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MiR-133 is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of mRNA translation/stability. Objective: To determine whether miR-133 affects βAR signaling during progression to heart failure. Methods and Results: Based on bioinformatic analysis, β1AR and other components of the β1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A (PKA), were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult CMs following selective β1AR stimulation. Furthermore, gain- and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic β1AR stimulation. This was confirmed in vivo using a novel cardiacspecific TetON-miR-133 inducible transgenic mouse model (Tg133). When subjected to transaortic constriction, Tg133 mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared to control mice. Conclusions: MiR-133 controls multiple components of the β1AR transduction cascade and is cardioprotective during heart failure.

Genomic and Proteomic Biomarkers That Distinguish Ischemic and Non-Ischemic Heart Failure and Subjects with Normal Cardiac Function

2007 ◽  
Vol 13 (6) ◽  
pp. S107
Author(s):  
Zsuzsanna Hollander ◽  
David Lin ◽  
Gabriela Cohen Freue ◽  
Janet Wilson-McManus ◽  
Robert Balshaw ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Ischemic Heart ◽  
Ischemic Heart Failure ◽  
Normal Cardiac Function

Polydatin attenuates cardiac hypertrophy through modulation of cardiac Ca2+ handling and calcineurin-NFAT signaling pathway

2014 ◽  
Vol 307 (5) ◽  
pp. H792-H802 ◽  
Author(s):  
Wenwen Ding ◽  
Ming Dong ◽  
Jianxin Deng ◽  
Dewen Yan ◽  
Yun Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Contractility ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Therapeutic Effects ◽  
Calcineurin Activity ◽  
Calcineurin Pathway

Polydatin (PD), a resveratrol glucoside extracted from the perennial herbage Polygonum cuspidatum, has been suggested to have wide cardioprotective effects. This study aimed to explore the direct antihypertrophic role of PD in cultured neonatal rat ventricular myocytes (NRVMs) and its therapeutic effects against pressure overload (PO)-induced hypertrophic remodeling and heart failure. Furthermore, we investigated the mechanisms underlying the actions of PD. Treatment of NRVMs with phenylephrine for 72 h induced myocyte hypertrophy, where the cell surface area and protein levels of atrial natriuretic peptide and β-myosin heavy chain (β-MHC) were significantly increased. The amplitude of systolic Ca2+ transient was increased, and sarcoplasmic reticulum Ca2+ recycling was prolonged. Concomitantly, calcineurin activity was increased and NFAT protein was imported into the nucleus. PD treatment restored Ca2+ handling and inhibited calcineurin-NFAT signaling, thus attenuating the hypertrophic remodeling in NRVMs. PO-induced cardiac hypertrophy was produced by transverse aortic constriction (TAC) in C57BL/6 mice, where the left ventricular posterior wall thickness and heart-to-body weight ratio were significantly increased. The cardiac function was increased at 5 wk of TAC, but significantly decreased at 13 wk of TAC. The amplitude of Ca2+ transient and calcineurin activity were increased at 5 wk of TAC. PD treatment largely abolished TAC-induced hypertrophic remodeling by inhibiting the Ca2+-calcineurin pathway. Surprisingly, PD did not inhibit myocyte contractility despite that the amplitude of Ca2+ transient was decreased. The cardiac function remained intact at 13 wk of TAC. In conclusion, PD is beneficial against PO-induced cardiac hypertrophy and heart failure largely through inhibiting the Ca2+-calcineurin pathway without compromising cardiac contractility.

Abstract 18575: The Transcriptional Cofactor Eyes Absent 4 is a Critical Regulator for Maintaining Normal Cardiac Function

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Tatjana Williams ◽  
Moritz Hundertmark ◽  
Peter Nordbeck ◽  
Sabine Voll ◽  
Anahi Paula Arias-Loza ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Cardiac Physiology ◽  
Eyes Absent ◽  
Age Dependent ◽  
Normal Cardiac Function

Introduction: E193, a human mutation in the transcription cofactor Eyes absent 4 (EYA4) causes hearing impairment followed by terminal heart failure, defining an important role for Eya4 in maintaining normal cardiac function. METHODS AND RESULTS: First, in-vitro experiments show that overexpression of Eya4 and the mutant isoform alter the expression of p27kip1 on both, transcript and protein levels. Next, we generated transgenic mice with cardiomyocyte-specific Eya4 or E193 overexpression to elucidate the in vivo function of Eya4 upon cardiac physiology. Luciferase and CHIP assays revealed that Eya4 and E193 bind to and regulate p27 expression in a contradictory manner, as already seen in vitro. Activity and phoshorylation of the downstream molecules CK2α and HDAC2 were significantly elevated in Eya4 mice, whereas they were significantly reduced in E193 animals compared to WT littermates. MRI and hemodynamic analysis indicate that a constitutive overexpression of Eya4 results in the age-dependent development of hypertrophy already under baseline conditions with no obvious functional effects, whereas E193 overexpressing animals develop onset of dilative cardiomyopathy as seen in human patients carrying the E193 mutation. Morphometric analysis proved ventricular hypertrophy or dilation of the LV associated with a thinning of the myocardial wall, interstitial fibrosis of myocardial tissue and alterations in cell size. Re-activation of fetal genes also occured in both TG models, characteristic for cardiac disease. Both cardiac phenotypes were aggravated upon pressure overload. Finally, we identified a new human heterozygous truncating Eya4 mutation, E215, which leads to similar clinical features of disease and a stable myocardial expression of the mutant protein. Conclusion: Our results implicate that Eya4 plays a critical role in regulating normal cardiac physiology and function via Six1/p27/CK2α/HDAC2 and that an imbalance within the Eya4/Six1 transcriptional complex leads to an age dependent onset of cardiomyopthy and heart failure.

Abstract MP170: Increased Ga o Expression Regulated by NRSF Plays a Key Role in the Development of Heart Failure Through the Impairment of Ca 2+ Homeostasis

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Hideaki Inazumi ◽  
Yasuaki Nakagawa ◽  
Kenji Moriuchi ◽  
Koichiro Kuwahara
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Troponin T ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Cardiac Gene ◽  
Normal Cardiac Function

Background: In the development of heart failure, pathological intracellular signaling reactivates fetal cardiac gene program, which leads to pathological cardiac remodeling. We previously reported that a transcriptional repressor, neuron restrictive silencer factor (NRSF) represses fetal cardiac gene program and maintains normal cardiac function, while pathological stimuli de-repress this NRSF mediated repression via activation of CaMKII. Molecular mechanisms by which NRSF maintains cardiac function remains to be determined, however. Purpose: To elucidate molecular mechanisms by which NRSF maintains normal cardiac function. Methods and Results: Newly generated cardiac-specific NRSF knockout mice (NRSF-cKO) showed cardiac dysfunction and premature deaths accompanied with lethal arrhythmias, as was observed in our previously reported cardiac-specific dominant-negative mutant of NRSF transgenic mice (dnNRSF-Tg). Expression of Gnao1 gene encoding Gα o , a member of inhibitory G proteins, was commonly increased in ventricles of dnNRSF-Tg and NRSF-cKO. ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay identified that NRSF transcriptionally regulates Gnao1 gene expression. Genetic Knockdown of Gα o in dnNRSF-Tg and NRSF-cKO ameliorated the reduced systolic function, increased arrhythmogenicity and reduced survival rates. Conversely cardiac-specific GNAO1 overexpression was sufficient to show impaired cardiac function. Mechanistically, Gα o increases current density in surface sarcolemmal L-type Ca 2 + channel and then activates CaMKII without affecting protein kinase A activity, which finally leads to impaired Ca 2+ handling and systolic dysfunction. Furthermore, expression of Gα o is also increased in ventricles of transverse aortic constriction model mice and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gα o prevented the progression of cardiac dysfunction. Conclusions: Increased expression of Gα o , induced by attenuation of NRSF-mediated repression forms a pathological circuit via activation of CaMKII and progresses heart failure by impairing Ca 2+ homeostasis. Gα o is a potential therapeutic target for heart failure.

“Physiological genomics”: mutant screens in zebrafish

1998 ◽  
Vol 275 (1) ◽  
pp. H1-H7 ◽  
Author(s):  
Kerri S. Warren ◽  
Mark C. Fishman
Keyword(s):  
Cardiovascular System ◽  
Danio Rerio ◽  
Large Scale ◽  
Normal Development ◽  
Single Gene ◽  
Gene Mutations ◽  
Genetic System ◽  
Developing Heart ◽  
Developmental Physiology ◽  
Large Scale Screening

Large-scale mutagenesis screens have proved essential in the search for genes that are important to development in the fly, worm, and yeast. Here we present the power of large-scale screening in a vertebrate, the zebrafish Danio rerio, and propose the use of this genetic system to address fundamental questions of vertebrate developmental physiology. As an example, we focus on zebrafish mutations that reveal single genes essential for normal development of the cardiovascular system. These single gene mutations disrupt specific aspects of rate, rhythm, conduction, or contractility of the developing heart.

4968Increased Gao expression underlies cardiac dysfunction and lethal arrhythmias accompanied with abnormal Ca2+ handling

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
H Inazumi ◽  
K Kuwahara ◽  
Y Kuwabara ◽  
Y Nakagawa ◽  
H Kinoshita ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Troponin T ◽  
Systolic Dysfunction ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Electrical Stability ◽  
Normal Cardiac Function

Abstract Background We previously demonstrated that a transcriptional repressor, neuron restrictive silencer factor (NRSF), maintains normal cardiac function and electrical stability. Transgenic mice expressing a dominant-negative mutant of NRSF in their hearts (dnNRSF-Tg) exhibit systolic dysfunction with cardiac dilation and premature death due to lethal arrhythmias like human dilated cardiomyopathy (DCM). Underlining mechanisms remain to be elucidated, however. Purpose We studied underling mechanisms by which NRSF maintains normal cardiac function to identify novel therapeutic targets for heart failure. Methods and results We generated cardiac-specific NRSF knockout mice (NRSFcKO) and confirmed that cardiac phenotypes of NRSFcKO are similar to those of dnNRSF-Tg. cDNA microarray analysis revealed that cardiac gene expression of GNAO1 that encodes Gαo, a member of inhibitory G protein Gαi family, is increased in both dnNRSF-Tg and NRSFcKO ventricles. We confirmed that GNAO1 is a direct target of NRSF through ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay. In dnNRSF-Tg, pharmacological inhibition of Gαo with pertussis toxin improved systolic dysfunction and knockdown of Gαo by crossing with GNAO1 knockout mice improved not only systolic function but also frequency of ventricular arrhythmias and survival rates. Electrophysiological and biochemical analysis in ventricular myocytes obtained from dnNRSF-Tg demonstrated that genetic reduction of Gαo ameliorated abnormalities in Ca2+ handling, which include increased current density in surface sarcolemmal L-type Ca2+ channel, reduced content of sarcoplasmic reticulum Ca2+ and lowered peak of Ca2+ transient. Furthermore, genetic reduction of Gαo attenuated increased phosphorylation levels of CAMKII in dnNRSF-Tg ventricles, which presumably underlies the improvement in Ca2+ handling. In addition, we identified increased Gαo expression in ventricles of heart failure model mice induced by transverse aortic constriction and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gαo ameliorated cardiac dysfunction. Figure 1 Conclusions We found that increased expression of Gαo, induced by attenuation of NRSF-mediated repression, plays a crucial role in the progression of cardiac dysfunction and lethal arrhythmias by evoking Ca2+ handling abnormality. These data demonstrate that Gαo is a potential therapeutic target for heart failure.

scholarly journals The Control of Diastolic Calcium in the Heart

2020 ◽  
Vol 126 (3) ◽  
pp. 395-412 ◽  
Author(s):  
David A. Eisner ◽  
Jessica L. Caldwell ◽  
Andrew W. Trafford ◽  
David C. Hutchings
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Reduced Ejection Fraction ◽  
Intracellular Ca ◽  
Cardiac Relaxation ◽  
Low Levels ◽  
Normal Cardiac Function

Normal cardiac function requires that intracellular Ca 2+ concentration be reduced to low levels in diastole so that the ventricle can relax and refill with blood. Heart failure is often associated with impaired cardiac relaxation. Little, however, is known about how diastolic intracellular Ca 2+ concentration is regulated. This article first discusses the reasons for this ignorance before reviewing the basic mechanisms that control diastolic intracellular Ca 2+ concentration. It then considers how the control of systolic and diastolic intracellular Ca 2+ concentration is intimately connected. Finally, it discusses the changes that occur in heart failure and how these may result in heart failure with preserved versus reduced ejection fraction.

Abstract 381: Mcur1 is a Potential Target to Modulate Cardiac Contractility and Alleviate Cardiac Function During Heart Failure

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Rajika Roy ◽  
Santhanam Shanmughapriya ◽  
Xueqian Zhang ◽  
Jianliang Song ◽  
Dhanendra Tomar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Dominant Negative ◽  
Selective Channel

Cardiac contractility is regulated by the intracellular Ca 2+ concentration fluxes which are actively regulated by multiple channels and transporters. Ca 2+ uptake into the mitochondrial matrix is precisely controlled by the highly Ca 2+ selective channel, Mitochondrial Calcium Uniporter (MCU). Earlier studies on the cardiac-specific acute MCU knockout and a transgenic dominant-negative MCU mice have demonstrated that mitochondrial Ca 2+ ( m Ca 2+ ) signaling is necessary for cardiac ‘‘fight-or-flight’’ contractile response, however, the role of m Ca 2+ buffering to shape global cytosolic Ca 2+ levels and affect E-C coupling, particularly the Ca 2+ transient, on a beat-to-beat basis still remains to be solved. Our earlier studies have demonstrated that loss of MCU Regulator 1 (MCUR1) in cardiomyocytes results in the impaired m Ca 2+ uptake. We have now employed the cardiac-specific MCUR1 knockout mouse to dissect the precise role of MCU in regulating cytosolic Ca 2+ transients associated with excitation-contraction (E-C) coupling and cardiac function. Results from our studies including the in vivo analyses of cardiac physiology during normal and pressure-overloaded mouse models and in vitro experiments including single-cell cardiac contractility, calcium transients, and electrophysiology measurements demonstrate that MCUR1/MCU regulated m Ca 2+ buffering in cardiomyocytes, although insignificant under basal condition, becomes critical in stress induced conditions and actively participates in regulating the c Ca 2+ transients. Also, the ablation of MCUR1 in cardiomyocytes during stress conditions prevents m Ca 2+ overload and subsequent mROS overproduction. Our data indicate that MCUR1 ablation offers protection against pressure-overload cardiac hypertrophy. In summary, our results provide critical insights into the mechanisms by which the MCU channel contributes in regulating the contractile function of the cardiomyocytes and the role of m Ca 2+ in the development and progression of heart failure.

Role of kinins in chronic heart failure and in the therapeutic effect of ACE inhibitors in kininogen-deficient rats

2000 ◽  
Vol 278 (2) ◽  
pp. H507-H514 ◽  
Author(s):  
Yun-He Liu ◽  
Xiao-Ping Yang ◽  
Dharmesh Mehta ◽  
Manohar Bulagannawar ◽  
Gloria M. Scicli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Infarct Size ◽  
Receptor Antagonist ◽  
Cardiac Remodeling ◽  
Myocardial Infarct ◽  
Brown Norway ◽  
Myocardial Infarct Size ◽  
Normal Cardiac Function

Using Brown Norway Katholiek (BNK) rats, which are deficient in kininogen (kinin precursor) due to a mutation in the kininogen gene, we examined the role of endogenous kinins in 1) normal cardiac function; 2) myocardial infarction (MI) caused by coronary artery ligation; 3) cardiac remodeling in the development of heart failure (HF) after MI; and 4) the cardioprotective effect of angiotensin-converting enzyme inhibitors (ACEI) on HF after MI. Two months after MI, rats were randomly treated with vehicle or the ACEI ramipril for 2 mo. Brown Norway rats (BN), which have normal kininogen, were used as controls. Left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), end-diastolic pressure (EDP), and ejection fraction (EF) as well as myocardial infarct size (IS), interstitial collagen fraction (ICF), cardiomyocyte cross-sectional area (MCA), and oxygen diffusion distance (ODD) were measured. We found that 1) cardiac hemodynamics, function, and histology were the same in sham-ligated BN and BNK rats; 2) IS was similar in BN and BNK; 3) in rats with HF treated with vehicle, the decrease in LVEF and the increase in LVEDV, LVESV, LVEDP, ICF, MCA, and ODD did not differ between BNK and BN; and 4) ACEI increased EF, decreased LVEDV and LVESV, and improved cardiac remodeling in BN-HF rats, and these effects were partially blocked by the bradykinin B2 receptor antagonist icatibant (HOE-140). In BNK-HF rats, ACEI failed to produce these beneficial cardiac effects. We concluded that in rats, lack of kinins does not influence regulation of normal cardiac function, myocardial infarct size, or development of HF; however, kinins appear to play an important role in the cardioprotective effect of ACEI, since 1) this effect was significantly diminished in kininogen-deficient rats and 2) it was blocked by a B2 kinin receptor antagonist in BN rats.

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