scholarly journals Zebrafish Heart Failure Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Suneeta Narumanchi ◽  
Hong Wang ◽  
Sanni Perttunen ◽  
Ilkka Tikkanen ◽  
Päivi Lakkisto ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Human Heart ◽  
Reverse Genetics ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Drug Induced ◽  
Failure Models ◽  
Human Heart Disease

Heart failure causes significant morbidity and mortality worldwide. The understanding of heart failure pathomechanisms and options for treatment remain incomplete. Zebrafish has proven useful for modeling human heart diseases due to similarity of zebrafish and mammalian hearts, fast easily tractable development, and readily available genetic methods. Embryonic cardiac development is rapid and cardiac function is easy to observe and quantify. Reverse genetics, by using morpholinos and CRISPR-Cas9 to modulate gene function, make zebrafish a primary animal model for in vivo studies of candidate genes. Zebrafish are able to effectively regenerate their hearts following injury. However, less attention has been given to using zebrafish models to increase understanding of heart failure and cardiac remodeling, including cardiac hypertrophy and hyperplasia. Here we discuss using zebrafish to study heart failure and cardiac remodeling, and review zebrafish genetic, drug-induced and other heart failure models, discussing the advantages and weaknesses of using zebrafish to model human heart disease. Using zebrafish models will lead to insights on the pathomechanisms of heart failure, with the aim to ultimately provide novel therapies for the prevention and treatment of heart failure.

scholarly journals ISCA1 Deficiency Induces Iron Metabolism Disorder and Myocardial Oncosis in Rat

2021 ◽  
Author(s):  
Yahao Ling ◽  
Xinlan Yang ◽  
Xu Zhang ◽  
Feifei Guan ◽  
Xiaolong Qi ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Iron Metabolism ◽  
Heart Development ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Pathological Process ◽  
Metabolism Disorder ◽  
Abnormal Metabolism ◽  
Validation Experiments

Abstract The effects of multiple mitochondrial dysfunction (MMD) on heart, a highly mitochondria-dependent tissue, is still unclear. This study was the first to verify the effect of ISCA1 gene deficiency, which has been shown to cause multiple mitochondrial dysfunction syndromes type 5 (MMDS5), on cardiac development in vivo, that is cardiomyocytes suffer from energy shortage due to abnormal metabolism of iron ion, which leads to oncosis and eventually HF and body death. Subsequently, we determine a new interacting molecule for ISCA1, six-transmembrane epithelial antigen of prostate 3 (STEAP3), which acts as a reductase in the reduction of Fe3+ to Fe2+. Forward and reverse validation experiments demonstrated that STEAP3 plays an important role in iron metabolism and energy generation impairment induced by ISCA1 deficiency. This result provides theoretical basis for understanding of MMDS pathogenesis, especially on heart development and the pathological process of heart diseases, and finally provides new clues for searching of clinical therapeutic targets.

Abstract 96: Inactivation of Neddylation Causes Left Ventricular Noncompaction Cardiomyopathy Through Suppressing YAP Signaling

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Jianqiu Zou ◽  
Wenxia Ma ◽  
Jie Li ◽  
Rodney Littlejohn ◽  
Il-man Kim ◽  
...  
Keyword(s):  
Cardiac Development ◽  
Heart Diseases ◽  
Left Ventricular ◽  
Late Gestation ◽  
Mouse Heart ◽  
Cardiomyocyte Proliferation ◽  
Transcription Cofactor ◽  
Wild Type Counterpart

Rationale: Cardiac development is orchestrated by a number of growth factors, transcription factors and epigenetic regulators, perturbation of which can lead to congenital heart diseases and cardiomyopathies. However, the role of novel ubiquitin-like protein modifiers, such as NEDD8 (neural precursor cells expressed developmentally downregulated 8), in cardiac development is unknown. Objectives: The objective of this study was to determine the significance of NEDD8 modification (neddylation) during perinatal cardiac development. Methods and Results: Neddylated proteins and NEDD8 enzymes were highly abundant in fetal and neonatal hearts but downregulated in adult hearts. We employed an αMHC Cre transgene to delete NAE1, a subunit of the NEDD8 E1 enzyme, in the perinatal mouse heart. Cardiac-specific deletion of NAE1 (NAE1 CKO ) significantly decreased neddylated proteins in the heart. The NAE1 CKO mice displayed cardiac hypoplasia, ventricular non-compaction and heart failure during late gestation, which became more pronounced by postnatal day 1 and led to perinatal lethality. Mechanistically, genetic deletion or pharmacological inhibition of NAE1 resulted in accumulation of Hippo kinases Mst1 and LATS1/2, which in turn phosphorylated and inactivated YAP, a transcription cofactor necessary for cardiomyocyte proliferation, leading to dysregulation of a number of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro . Reactivation of YAP signaling by overexpression of a constitutively-active YAP mutant (YAP 5SA ), but not its wild-type counterpart, overcame the blockade of cardiomyocyte proliferation induced by inhibition of NAE1. Conclusions: Our findings establish the importance of neddylation in the heart, more specifically, in ventricular chamber maturation, and identify neddylation as a novel regulator of Hippo-YAP signaling to promote cardiomyocyte proliferation.

scholarly journals Intracellular Dyssynchrony of Diastolic Cytosolic [Ca 2+ ] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure

2013 ◽  
Vol 113 (5) ◽  
pp. 527-538 ◽  
Author(s):  
Felix Hohendanner ◽  
Senka Ljubojević ◽  
Niall MacQuaide ◽  
Michael Sacherer ◽  
Simon Sedej ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Human Heart ◽  
Cyclopiazonic Acid ◽  
Cardiomyocyte Hypertrophy ◽  
Human Heart Failure ◽  
Mitochondrial Density ◽  
Human Cardiomyocytes ◽  
End Stage ◽  
The Impact

Rationale : Synchronized release of Ca 2+ into the cytosol during each cardiac cycle determines cardiomyocyte contraction. Objective: We investigated synchrony of cytosolic [Ca 2+ ] decay during diastole and the impact of cardiac remodeling. Methods and Results: Local cytosolic [Ca 2+ ] transients (1-µm intervals) were recorded in murine, porcine, and human ventricular single cardiomyocytes. We identified intracellular regions of slow (slowCaR) and fast (fastCaR) [Ca 2+ ] decay based on the local time constants of decay (TAU local ). The SD of TAU local as a measure of dyssynchrony was not related to the amplitude or the timing of local Ca 2+ release. Stimulation of sarcoplasmic reticulum Ca 2+ ATPase with forskolin or istaroxime accelerated and its inhibition with cyclopiazonic acid slowed TAU local significantly more in slowCaR, thus altering the relationship between SD of TAU local and global [Ca 2+ ] decay (TAU global ). Na + /Ca 2+ exchanger inhibitor SEA0400 prolonged TAU local similarly in slowCaR and fastCaR. FastCaR were associated with increased mitochondrial density and were more sensitive to the mitochondrial Ca 2+ uniporter blocker Ru360. Variation in TAU local was higher in pig and human cardiomyocytes and higher with increased stimulation frequency (2 Hz). TAU local correlated with local sarcomere relengthening. In mice with myocardial hypertrophy after transverse aortic constriction, in pigs with chronic myocardial ischemia, and in end-stage human heart failure, variation in TAU local was increased and related to cardiomyocyte hypertrophy and increased mitochondrial density. Conclusions: In cardiomyocytes, cytosolic [Ca 2+ ] decay is regulated locally and related to local sarcomere relengthening. Dyssynchronous intracellular [Ca 2+ ] decay in cardiac remodeling and end-stage heart failure suggests a novel mechanism of cellular contractile dysfunction.

scholarly journals Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease

2020 ◽  
Author(s):  
Yonatan Lewis-Israeli ◽  
Aaron Wasserman ◽  
Mitchell Gabalski ◽  
Kristen Ball ◽  
Brett Volmert ◽  
...  
Keyword(s):  
Self Assembly ◽  
Human Heart ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Defects ◽  
Cellular Level ◽  
Human Model ◽  
Defined Culture

Abstract Congenital heart defects (CHD) constitute the most common birth defect in humans, affecting approximately 1% of all live births. Our ability to understand how these disorders originate is hindered by our limited ability to model the complexity of the human heart in vitro. There is a pressing need to develop more faithful organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here we report a novel method to generate human heart organoids by self-assembly using pluripotent stem cells. Our method is fully defined, highly efficient, scalable, shows high reproducibility and is compatible with screening and high-throughput approaches. Human heart organoids (hHOs) are generated using a two-step canonical Wnt signaling modulation strategy using a combination of chemical inhibitors and growth factors in completely defined culture conditions. hHOs faithfully recapitulate human cardiac development and are similar to age-matched fetal cardiac tissues at the transcriptomic, structural and cellular level. hHOs develop sophisticated internal chambers with well-organized multi-lineage cell-type regional identities reminiscent of the heart fields and the atrial and ventricular chambers, as well as the epicardium, endocardium, and coronary vasculature, and exhibit functional activity. We also show that hHOs can recreate complex metabolic disorders associated with CHD by establishing the first in vitro human model of diabetes during pregnancy (DDP) to study embryonic CHD. morphological and metabolically effects of increased glucose and insulin, showing the capability of modeling the effects of diabetes during pregnancy (DDP). Our heart organoid model constitutes a powerful novel tool for translational studies in human cardiac development and disease.

Abstract 379: Inhibition of Bcl-x Phosphorylation Prevents Cardiomyocyte Death, Cardiac Remodeling and Heart Failure After Myocardial Infarction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Michinari Nakamura ◽  
Peiyong Zhai ◽  
Dominic D Re ◽  
Junichi Sadoshima
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Remodeling ◽  
Ischemia Reperfusion ◽  
Resistant Mutant ◽  
Cardiac Contraction ◽  
Dependent Manner ◽  
Infarct Area

Cardiac remodeling promotes heart failure (HF). Cardiomyocyte (CM) death is one of the mechanisms to develop cardiac remodeling. We recently reported that Mst1 phosphorylates Bcl-xL at Ser14, which promotes apoptosis by inducing dissociation of Bcl-xL from Bax and consequent activation of Bax in CMs. Its phosphorylation is increased in response to ischemia-reperfusion (IR) in an Mst1-dependent manner. However, the functional significance of endogenous Bcl-xL phosphorylation remains unclear in vivo. To address this question, knock-in (KI) mice with alanine mutation at Ser14 in Bcl-x were generated. At baseline, cardiac function was similar between wild-type (WT) and heterozygous KI (HKI) mice (EF 76% and 79%, respectively). HKI mice exhibited smaller % infarct area (30%) than WT (43%) (p=0.016) upon IR, suggesting that phosphorylation of endogenous Bcl-xL at Ser14 plays an essential role in mediating IR injury. In order to test the role of Bcl-xL phosphorylation in the development of HF, HKI and WT mice were subjected to permanent ligation of LAD for 4 weeks. During progression of cardiac remodeling, Mst1 was activated in both WT and HKI mice. Phosphorylation of Bcl-xL and Bcl-xS, an alternative transcriptional variant of Bcl-x, both at Ser14, were increased in WT mice, which were abrogated in HKI mice. The infarct area evaluated with TTC staining at Day 1 was similar in WT and HKI mice (59.1% and 61.2%, p=0.65). Four weeks after myocardial infarction (MI), WT mice exhibited lower cardiac contraction (EF 46.5%) and higher LVEDP (10.8mmHg) than those in HKI mice (EF 68.9% and LVEDP 7.0mmHg) (both p<0.05). Scar area and TUNEL-positive CMs were greater in WT (49.0% and 1.6%, respectively) than in HKI mice (29.2% and 0.4%, respectively) (both p<0.05). Cleaved caspase 3 and 9 were significantly increased (3.2- and 5.7-fold, respectively) in WT but not in HKI mice. In vitro experiments with overexpression of phospho-mimicking mutant (Bcl-xS-S14D) showed 13% reduction in cell viability compared with that of phospho-resistant mutant (Bcl-xS-S14A) (p=0.01%). Our results suggest that phosphorylation of Bcl-xL and Bcl-xS at Ser14 contributes to CM death in response to IR and chronic MI in vivo, thereby promoting cardiac remodeling and HF.

scholarly journals Dysregulated micro-RNAs and long noncoding RNAs in cardiac development and pediatric heart failure

2020 ◽  
Vol 318 (5) ◽  
pp. H1308-H1315 ◽  
Author(s):  
Lee Toni ◽  
Frehiwet Hailu ◽  
Carmen C. Sucharov
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cardiovascular Diseases ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Regulation Of Gene Expression ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Cardiovascular Development ◽  
Micro Rnas

Noncoding RNAs (ncRNAs) are broadly described as RNA molecules that are not translated into protein. The investigation of dysregulated ncRNAs in human diseases such as cancer, neurological, and cardiovascular diseases has been under way for well over a decade. Micro-RNAs and long noncoding RNAs (lncRNAs) are the best characterized ncRNAs. These ncRNAs can have profound effects on the regulation of gene expression during cardiac development and disease. Importantly, ncRNAs are significant regulators of gene expression in several congenital heart diseases and can positively or negatively impact cardiovascular development. In this review, we focus on literature involving micro-RNAs and lncRNAs in the context of pediatric cardiovascular diseases, preclinical models of heart failure, and cardiac development.

Abstract 313: Interleukin-6 Mediates Concentric Hypertrophy, Diastolic Dysfunction and Myocardial Fibrosis in Rats

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Giselle C Melendez ◽  
Yan Du ◽  
Joseph S Janicki ◽  
Gregory L Brower
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Myocardial Fibrosis ◽  
Interleukin 6 ◽  
Cardiac Remodeling ◽  
Cardiomyocyte Hypertrophy ◽  
Myocardial Remodeling ◽  
Concentric Hypertrophy ◽  
Tnf Α

Induction of inflammatory cytokines has been implicated in the progression of myocardial remodeling and heart failure (HF). Increased levels of circulating TNF-α and interleukin-6 (IL-6) in patients with HF, suggest that these cytokines may be involved in the pathogenesis of heart disease. In previous studies we have shown that TNF-α is an important contributor to the adverse myocardial remodeling. TNF-α is known to mediate collagen degradation as well as in-series sarcomeric addition contributing to ventricular dilatation. However, the effects of IL-6 on cardiac remodeling in vivo have not been investigated. Accordingly, in this study we explore the hypothesis that up-regulation of IL-6 mediates adverse myocardial remodeling. To this end, a group of adult male Sprague Dawley rats was infused with IL-6 (2.5 μg/kg/hr, IP) for 7 days via osmotic minipump and compared to aged-matched shams. LV pressure, size, and function were measured using a blood-perfused isolated heart preparation. At the end of the experiment, hearts were weighed and analyzed for collagen volume fraction (CVF) and isolated cardiomyocyte size. The EDP-EDV (End Diastolic Pressure and Volume) relationship provided that IL-6 infusion produced LV stiffness and a clear tendency for a shift of the EDP-EDV curve to the left due to ventricular hypertrophy and diastolic dysfunction. LV weight differences demonstrate concentric hypertrophy (749 mg versus 660 mg in control hearts; p< 0.05) and a marked increase in interstitial collagen in the IL-6 infused hearts relative to that in control hearts (CVF of 6.2% vs. 1.7%, respectively; p< 0.001). The cardiomyocyte hypertrophy at the cellular level also reflected a concentric phenotype, with cells being significantly longer and thicker (18% and 32%, respectively; p< 0.01). These novel observations demonstrate a direct effect of IL-6 on cardiac remodeling in vivo, which in contrast to TNF-α, induces a dramatic myocardial fibrosis together with concentric cardiac hypertrophy. This suggests that IL-6 may contribute to the development of diastolic dysfunction, and as such could drive the transition to heart failure.

Abstract 1409: Molecular Imaging of Post-Infarction Cardiac Remodeling and Effects of Anti-Angiotensin Therapy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Susanne W Van Den Borne ◽  
Satoshi Isobe ◽  
Johan Verjans ◽  
Artiom Petrov ◽  
Dagfinn Lovhaug ◽  
...  
Keyword(s):  
Heart Failure ◽  
Molecular Imaging ◽  
Cardiac Remodeling ◽  
Interstitial Fibrosis ◽  
Coronary Artery Occlusion ◽  
Tracer Uptake ◽  
Border Zone ◽  
Collagen Deposition ◽  
Infarct Area

Background. Collagen deposition and interstitial fibrosis contribute to development of cardiac remodeling and heart failure (HF) after myocardial infarction (MI). We used Tc-99m-labeled Cy5.5-RGD imaging peptide (CRIP), for molecular imaging of the extent of collagen deposition. Methods. Of 46 Swiss-Webster mice, (MI) was induced in 41 by left coronary artery occlusion and 5 mice were imaged unmanipulated. Of these, 6, 6, and 5 mice, received intravenous CRIP for micro-SPECT/micro-CT imaging in vivo after 2, 4, and 12 weeks of MI. Eight mice received captopril or captopril with losartan for 4 weeks following MI before CRIP imaging for the assessment of effect of anti-angiotensin therapy on collagen deposition. To evaluate the specificity of the probe, 6 animals received scrambled peptide 4 weeks after MI. The remaining 10/46 mice, received CRIP without a radiolabel after 2 weeks of MI for histological characterization of tracer uptake by two-photon microscopy. Results. Distinct myocardial CRIP uptake was observed in the infarct area and border zone. The quantitative uptake in the infarct area, expressed as percent injected dose per gram (%ID/g), was highest in mice at 2 weeks (2.75±0.46%), followed by 4 (2.26±0.09%), and 12 weeks (1.74±0.24%) after MI as compared to uptake in sham-operated mice (0.59±0.19%). In the peri-infarct and remote areas, the uptake was higher at 12 weeks. The histologic characterization revealed specificity of the probe for replacement, interstitial and perivascular fibrosis. Captopril (1.78±0.31%) and combination of captopril and losartan (1.13±0.28%) significantly decreased radiotracer uptake in the infarct. The uptake of scrambled peptide (0.74 ±0.17%) was similar to CRIP uptake in normal myocardium. Conclusions. Radiolabeled CRIP allows for noninvasive visualization of interstitial alterations during cardiac remodeling. The CRIP uptake is significantly reduced with captopril and losartan treatment. If proven clinically feasible, such a strategy would help identify and prevent evolution of heart failure in post-MI patients.

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