scholarly journals Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model for Phospholamban R14del cardiomyopathy

2020 ◽  
Author(s):  
S.M. Kamel ◽  
C.J.M. van Opbergen ◽  
C.D. Koopman ◽  
A.O. Verkerk ◽  
Y. L. Onderwater ◽  
...  
Keyword(s):  
Structural Changes ◽  
Cellular Level ◽  
Zebrafish Model ◽  
Physiological Processes ◽  
Cardiac Contractile ◽  
Age Related ◽  
Intracellular Ca ◽  
Cardiac Contractile Dysfunction ◽  
Novel Drug

AbstractThe heterozygous phospholamban (PLN) p.Arg14del (R14del) mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. The PLN R14del mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca2+ dynamics. Little is known about the physiological processes preceding PLN R14del induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we addressed these issues using a knock-in PLN R14del zebrafish model. Hearts from adult zebrafish with the R14del mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography revealed contractile pulsus alternans before overt structural changes occurred, which correlated at the cellular level with action potential duration (APD) alternans. These functional alterations are preceded by diminished Ca2+ transient amplitudes in embryonic hearts. We found that istaroxime treatment ameliorates the in vivo Ca2+ dysregulation, rescues the cellular APD alternans, while it improves cardiac relaxation. Thus, we present novel insight into the pathophysiology of PLN R14del cardiomyopathy and identify istaroxime as a potential novel drug for its treatment.

scholarly journals Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
S. M. Kamel ◽  
C. J. M. van Opbergen ◽  
C. D. Koopman ◽  
A. O. Verkerk ◽  
B. J. D. Boukens ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Structural Changes ◽  
Cellular Level ◽  
Zebrafish Model ◽  
Cardiac Contractile ◽  
Age Related ◽  
Intracellular Ca ◽  
Cardiac Contractile Dysfunction

AbstractThe heterozygous Phospholamban p.Arg14del mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. This mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca2+ dynamics. Little is known about the physiological processes preceding induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we address these issues using a knock-in Phospholamban p.Arg14del zebrafish model. Hearts from adult zebrafish with this mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography reveals contractile variations before overt structural changes occur, which correlates at the cellular level with action potential duration alternans. These functional alterations are preceded by diminished Ca2+ transient amplitudes in embryonic hearts as well as an increase in diastolic Ca2+ level, slower Ca2+ transient decay and longer Ca2+ transients in cells of adult hearts. We find that istaroxime treatment ameliorates the in vivo Ca2+ dysregulation, rescues the cellular action potential duration alternans, while it improves cardiac relaxation. Thus, we present insight into the pathophysiology of Phospholamban p.Arg14del cardiomyopathy.

scholarly journals Zebrafish Model in Ophthalmology to Study Disease Mechanism and Drug Discovery

2021 ◽  
Vol 14 (8) ◽  
pp. 716
Author(s):  
Yiwen Hong ◽  
Yan Luo
Keyword(s):  
Drug Discovery ◽  
Behavioral Assessment ◽  
Age Related Macular Degeneration ◽  
Disease Mechanism ◽  
Zebrafish Model ◽  
Age Related ◽  
Eye Disorders ◽  
Vertebrate Model ◽  
Drug Treatments ◽  
Novel Drug

Visual impairment and blindness are common and seriously affect people’s work and quality of life in the world. Therefore, the effective therapies for eye diseases are of high priority. Zebrafish (Danio rerio) is an alternative vertebrate model as a useful tool for the mechanism elucidation and drug discovery of various eye disorders, such as cataracts, glaucoma, diabetic retinopathy, age-related macular degeneration, photoreceptor degeneration, etc. The genetic and embryonic accessibility of zebrafish in combination with a behavioral assessment of visual function has made it a very popular model in ophthalmology. Zebrafish has also been widely used in ocular drug discovery, such as the screening of new anti-angiogenic compounds or neuroprotective drugs, and the oculotoxicity test. In this review, we summarized the applications of zebrafish as the models of eye disorders to study disease mechanism and investigate novel drug treatments.

scholarly journals In Vitro and in Vivo Imaging of Nitroxyl with Copper Fluorescent Probe in Living Cells and Zebrafish

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2551 ◽  
Author(s):  
Sathyadevi Palanisamy ◽  
Yu-Liang Wang ◽  
Yu-Jen Chen ◽  
Chiao-Yun Chen ◽  
Fu-Te Tsai ◽  
...  
Keyword(s):  
Critical Role ◽  
Model Organism ◽  
Living Cells ◽  
Biological Species ◽  
Zebrafish Model ◽  
Physiological Processes ◽  
Collective Data ◽  
Angeli's Salt

Nitroxyl (HNO) plays a critical role in many physiological processes which includes vasorelaxation in heart failure, neuroregulation, and myocardial contractility. Powerful imaging tools are required to obtain information for understanding the mechanisms involved in these in vivo processes. In order to develop a rapid and high sensitive probe for HNO detection in living cells and the zebrafish model organism, 2-((2-(benzothiazole-2yl)benzylidene) amino)benzoic acid (AbTCA) as a ligand, and its corresponding copper(II) complex Cu(II)-AbTCA were synthesized. The reaction results of Cu(II)-AbTCA with Angeli’s salt showed that Cu(II)-AbTCA could detect HNO quantitatively in a range of 40–360 µM with a detection limit of 9.05 µM. Furthermore, Cu(II)-AbTCA is more selective towards HNO over other biological species including thiols, reactive nitrogen, and reactive oxygen species. Importantly, Cu(II)-AbTCA was successfully applied to detect HNO in living cells and zebrafish. The collective data reveals that Cu(II)-AbTCA could be used as a potential probe for HNO detection in living systems.

scholarly journals A novel mitochondrial enriched antioxidant protects neurons against acute oxidative stress

2017 ◽  
Author(s):  
Nicola J. Drummond ◽  
Nick O. Davies ◽  
Janet E. Lovett ◽  
Mark R. Miller ◽  
Graeme Cook ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Damage ◽  
Radical Scavenging ◽  
Head Group ◽  
Neural Cells ◽  
Zebrafish Model ◽  
Free System ◽  
Age Related

AbstractExcessive reactive oxygen species (ROS) can damage proteins, lipids, and DNA, which result in cell damage and death. The outcomes can be acute, as seen in stroke, or more chronic as observed in age-related diseases such as Parkinson’s disease. Here we investigate the antioxidant ability of a novel synthetic flavonoid, Proxison (7-decyl-3-hydroxy-2-(3,4,5-trihydroxyphenyl)-4-chromenone), using a range of in vitro and in vivo approaches. We show that, while it has radical scavenging ability on par with other flavonoids in a cell-free system, Proxison is orders of magnitude more potent than natural flavonoids at protecting neural cells against oxidative stress and is capable of rescuing damaged cells. The unique combination of a lipophilic hydrocarbon tail with a modified polyphenolic head group promotes efficient cellular uptake and mitochondrial localisation of Proxison. Importantly, in vivo administration of Proxison demonstrated effective and well tolerated neuroprotection against oxidative stress in a zebrafish model of dopaminergic neuronal loss.

scholarly journals Electrical Stimulation Activates Fibroblasts through the Elevation of Intracellular Free Ca2+: Potential Mechanism of Pelvic Electrical Stimulation Therapy

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Suting Li ◽  
Danhua Lu ◽  
Jianming Tang ◽  
Jie Min ◽  
Ming Hu ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Nuclear Translocation ◽  
Low Voltage ◽  
Second Messenger ◽  
Vaginal Wall ◽  
Downstream Signaling ◽  
Physiological Processes ◽  
L929 Fibroblast ◽  
Intracellular Ca

Ca2+ is an important ion in response to electrical stimulation (ES) and acts as second messenger in the regulation of various physiological processes. Pelvic floor electrical stimulation (PES) is a low-voltage clinical application, available for urinary incontinence (UI) treatment. Fibroblasts, as the main cellular component of vaginal wall and pelvic ligament, play an important role in the maintenance of pelvic health. We studied the effect of ES on fibroblasts in this study. ES was conducted with electrotaxis chambers on L929 fibroblast and the ES parameter was 100 mV/mm×2h. The results showed that ES increased intracellular Ca2+ concentration, promoted the expression of PCNA, CyclinB1, and CyclinD1, and increased the proportion of cells in S and G2 phages. After ES, fibroblasts get activated and proliferated. Besides, BAPTA-AM, a membrane permeated chelator for intracellular free Ca2+, partially inhibited the effect of ES on fibroblasts activation and proliferation promotion. Furthermore, we elucidated that Ca2+, as a second messenger and upstream signal for Smads and Akt signaling, regulated ES-induced nuclear translocation of smad2/3, phosphorylation of smad2/3, Akt, and GSK3β. Finally, we validated the effect of ES on PES mouse model. The results indicated that PES promoted the activation and proliferation of fibroblasts in vivo. In conclusion, we verify that ES can elevate the concentration of intracellular Ca2+ and activate its downstream signaling and then promote the activation of fibroblasts, which may be one of the mechanisms of PES therapy.

scholarly journals Electromechanical and structural alterations in the aging rabbit heart and aorta

2012 ◽  
Vol 302 (8) ◽  
pp. H1625-H1635 ◽  
Author(s):  
Leroy L. Cooper ◽  
Katja E. Odening ◽  
Min-Sig Hwang ◽  
Leonard Chaves ◽  
Lorraine Schofield ◽  
...  
Keyword(s):  
Conduction Velocity ◽  
Structural Changes ◽  
Optical Mapping ◽  
Diastolic Pressure ◽  
Ex Vivo ◽  
Rabbit Model ◽  
Systolic Pressure ◽  
Age Related ◽  
Sheet Structure

Aging increases the risk for arrhythmias and sudden cardiac death (SCD). We aimed at elucidating aging-related electrical, functional, and structural changes in the heart and vasculature that account for this heightened arrhythmogenic risk. Young (5–9 mo) and old (3.5–6 yr) female New Zealand White (NZW) rabbits were subjected to in vivo hemodynamic, electrophysiological, and echocardiographic studies as well as ex vivo optical mapping, high-field magnetic resonance imaging (MRI), and histochemical experiments. Aging increased aortic stiffness (baseline pulse wave velocity: young, 3.54 ± 0.36 vs. old, 4.35 ± 0.28 m/s, P < 0.002) and diastolic (end diastolic pressure-volume relations: 3.28 ± 0.5 vs. 4.95 ± 1.5 mmHg/ml, P < 0.05) and systolic (end systolic pressure-volume relations: 20.56 ± 4.2 vs. 33.14 ± 8.4 mmHg/ml, P < 0.01) myocardial elastances in old rabbits. Electrophysiological and optical mapping studies revealed age-related slowing of ventricular and His-Purkinje conduction (His-to-ventricle interval: 23 ± 2.5 vs. 31.9 ± 2.9 ms, P < 0.0001), altered conduction anisotropy, and a greater inducibility of ventricular fibrillation (VF, 3/12 vs. 7/9, P < 0.05) in old rabbits. Histochemical studies confirmed an aging-related increased fibrosis in the ventricles. MRI showed a deterioration of the free-running Purkinje fiber network in ventricular and septal walls in old hearts as well as aging-related alterations of the myofibrillar orientation and myocardial sheet structure that may account for this slowed conduction velocity. Aging leads to parallel stiffening of the aorta and the heart, including an increase in systolic stiffness and contractility and diastolic stiffness. Increasingly, anisotropic conduction velocity due to fibrosis and altered myofibrillar orientation and myocardial sheet structure may contribute to the pathogenesis of VF in old hearts. The aging rabbit model represents a useful tool for elucidating age-related changes that predispose the aging heart to arrhythmias and SCD.

scholarly journals Loss of D2 Receptor Binding with Age in Rhesus Monkeys: Importance of Correction for Differences in Striatal Size

1999 ◽  
Vol 19 (2) ◽  
pp. 218-229 ◽  
Author(s):  
Evan D. Morris ◽  
Svetlana I. Chefer ◽  
Mark A. Lane ◽  
Raymond F. Muzic ◽  
Dean F. Wong ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Rhesus Monkeys ◽  
Structural Changes ◽  
D2 Receptor ◽  
Binding Potential ◽  
Age Related ◽  
Positron Emission ◽  
Dopamine Receptor Binding

The relation between striatal dopamine D2 receptor binding and aging was investigated in rhesus monkeys with PET. Monkeys (n = 18, 39 to 360 months of age) were scanned with 11C-raclopride; binding potential in the striatum was estimated graphically. Because our magnetic resonance imaging analysis revealed a concomitant relation between size of striatum and age, the dynamic positron emission tomography (PET) data were corrected for possible partial volume (PV) artifacts before parameter estimation. The age-related decline in binding potential was 1% per year and was smaller than the apparent effect if the age-related change in size was ignored. This is the first in vivo demonstration of a decline in dopamine receptor binding in nonhuman primates. The rate of decline in binding potential is consistent with in vitro findings in monkeys but smaller than what has been measured previously in humans using PET. Previous PET studies in humans, however, have not corrected for PV error, although a decline in striatal size with age has been demonstrated. The results of this study suggest that PV correction must be applied to PET data to accurately detect small changes in receptor binding that may occur in parallel with structural changes in the brain.

Abstract 13725: Limited Fatty Acid Use by CD36 Deficiency Accelerates the Development of Diabetic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ryo Kawakami ◽  
Yogi Umbarawan ◽  
Tatsuya Iso ◽  
Norimichi Koitabashi ◽  
Hiroaki Sunaga ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Diabetic Cardiomyopathy ◽  
Energy Demand ◽  
Tca Cycle ◽  
Contractile Dysfunction ◽  
Transmembrane Glycoprotein ◽  
Cardiac Contractile ◽  
Cardiac Contractile Dysfunction ◽  
Systolic And Diastolic Function

Diabetes is an independent risk factor for the development of heart failure. In diabetic hearts, it has been reported that increased fatty acid (FA) uptake and deranged FA use result in accumulation of cardiotoxic lipids and reduced cardiac efficiency that compromise systolic and diastolic function. To date, lipotoxicity hypothesis is prevailing as a key event driving diabetic cardiomyopathy and it is proposed that limited FA use is beneficial for diabetic hearts. However, it has not been fully studied whether limited FA use is actually beneficial in-vivo beating hearts in diabetes. CD36, a transmembrane glycoprotein, has a major role in FA uptake in the heart. CD36 knockout (CD36KO) hearts exhibit reduced rates of FA transport and oxidation with marked enhancement of glucose use. In this study, we explored whether reduced FA use by CD36 ablation suppresses the development of streptozotocin (STZ)-induced diabetic cardiomyopathy. Contrary to our expectations, we found that cardiac contractile dysfunction was deteriorated 16 weeks after STZ treatment in CD36KO mice. Although accelerated glucose uptake, estimated by 18 F-FDG uptake, was not reduced in CD36KO-STZ hearts, total energy supply, estimated by the pool size of the TCA cycle, was significantly reduced in CD36KO-STZ hearts. Isotopomer analysis with 13 C 6 -glucose revealed that accelerated glycolysis, estimated by enrichment of 13 C 3 -lactate, 13 C 2 -alanine, 13 C 2 -citrate and 13 C 2 -malate, in CD36KO hearts was markedly suppressed by STZ treatment. On the other hand, levels of ceramides, cardiotoxic lipids from excessive FA, were not elevated in CD36KO-STZ hearts compared to WT-STZ. Further, increased energy demand induced by transverse aortic constriction resulted in synergistic exacerbation of cardiac contractile dysfunction in CD36KO-STZ mice. These findings suggest that CD36KO-STZ hearts are energetically compromised by reduced FA use and suppressed glycolysis, leading to cardiac contractile dysfunction. Therefore, it is very likely that enhanced FA use in diabetic hearts occurs to compensate for reduced glucose use, and that limitation of FA utilization could be detrimental to the development of diabetic cardiomyopathy.

scholarly journals Endocannabinoids acting at CB1receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats

2007 ◽  
Vol 293 (3) ◽  
pp. H1689-H1695 ◽  
Author(s):  
Sándor Bátkai ◽  
Partha Mukhopadhyay ◽  
Judith Harvey-White ◽  
Raouf Kechrid ◽  
Pál Pacher ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Liver Cirrhosis ◽  
Cardiac Contractility ◽  
Receptor Expression ◽  
Contractile Dysfunction ◽  
Cirrhotic Cardiomyopathy ◽  
Cardiac Contractile ◽  
Cardiac Contractile Dysfunction

Advanced liver cirrhosis is associated with hyperdynamic circulation consisting of systemic hypotension, decreased peripheral resistance, and cardiac dysfunction, termed cirrhotic cardiomyopathy. Previous studies have revealed the role of endocannabinoids and vascular CB1receptors in the development of generalized hypotension and mesenteric vasodilation in animal models of liver cirrhosis, and CB1receptors have also been implicated in the decreased β-adrenergic responsiveness of isolated heart tissue from cirrhotic rats. Here we document the cardiac contractile dysfunction in vivo in liver cirrhosis and explore the role of the endocannabinoid system in its development. Rats with CCl4-induced cirrhosis developed decreased cardiac contractility, as documented through the use of the Millar pressure-volume microcatheter system, low blood pressure, and tachycardia. Bolus intravenous injection of the CB1antagonist AM251 (3 mg/kg) acutely increased mean blood pressure, as well as both load-dependent and -independent indexes of systolic function, whereas no such changes were elicited by AM251 in control rats. Furthermore, tissue levels of the endocannabinoid anandamide increased 2.7-fold in the heart of cirrhotic compared with control rats, without any change in 2-arachidonoylglycerol levels, whereas, in the cirrhotic liver, both 2-arachidonoylglycerol (6-fold) and anandamide (3.5-fold) were markedly increased. CB1-receptor expression in the heart was unaffected by cirrhosis, as verified by Western blotting. Activation of cardiac CB1receptors by endogenous anandamide contributes to the reduced cardiac contractility in liver cirrhosis, and CB1-receptor antagonists may be used to improve contractile function in cirrhotic cardiomyopathy and, possibly, in other forms of heart failure.

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