scholarly journals Atypical ALPK2 kinase is not essential for cardiac development and function

2020 ◽  
Vol 318 (6) ◽  
pp. H1509-H1515
Author(s):  
Julius Bogomolovas ◽  
Wei Feng ◽  
Matthew Daniel Yu ◽  
Serena Huang ◽  
Lunfeng Zhang ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Development ◽  
Cardiac Defects ◽  
Cardiac Phenotype ◽  
Cardiac Functions ◽  
And Function

Several studies indicated the importance of ALPK2 for cardiac function and development. A recent study in zebrafish report that loss of ALPK2 leads to severe cardiac defects. In contrast, murine Alpk2-gKO models developed in this work display no overt cardiac phenotype. Our results suggest ALPK2, as a rapidly evolving gene, lost its essential cardiac functions in mammals.

scholarly journals Abnormal Cardiac Development in the Absence of Heart Glycogen

2004 ◽  
Vol 24 (16) ◽  
pp. 7179-7187 ◽  
Author(s):  
Bartholomew A. Pederson ◽  
Hanying Chen ◽  
Jill M. Schroeder ◽  
Weinian Shou ◽  
Anna A. DePaoli-Roach ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Glycogen Synthase ◽  
Heart Defects ◽  
Mendelian Inheritance ◽  
And Function ◽  
Impaired Cardiac Function

ABSTRACT Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ∼90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

Abstract 278: Cardiac Med1 is Necessary for Postnatal Survival in Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kathryn M Spitler ◽  
Jessica M Ponce ◽  
Duane D Hall ◽  
Chad E Grueter
Keyword(s):  
Cardiovascular Disease ◽  
Cardiac Function ◽  
Gene Transcription ◽  
Cardiac Development ◽  
Critical Role ◽  
Cardiac Contractility ◽  
Mediator Complex ◽  
Cardiomyocyte Hypertrophy ◽  
And Function

Alterations in gene transcription are commonly associated with cardiovascular disease pathogenesis characterized by cardiomyocyte hypertrophy. The phenotypic responses result in diminished cardiac contractility, ventricular dilation, fibrosis and ultimately sudden death. The mediator complex is a crucial facilitator of gene transcription; however, few studies have investigated the role of mediator in cardiovascular disease initiation and progression. A key subunit of the Mediator complex, MED1, interacts with nuclear receptors to target gene-specific transcription. To determine the role of MED1 in regulating cardiac function, we generated a heart specific knockout of MED1 (cMED1KO). Postnatal deletion of MED1 in mice results in lethality between 3 to 6 weeks of age. The cMED1KO mice display a marked increase in heart mass compared to floxed controls. Furthermore, echocardiography and histological analysis of hearts taken at 3 weeks showed that the cMED1KO animals had decreased cardiac function, increased fibrosis and a dilated left ventricle. Transcriptional changes were observed for key markers of cardiac disease including MYH7, ANF, ACTIN1. We performed RNAseq analysis to identify changes in the transciptome between cMED1KO and floxed control hearts. The analysis unveiled changes in expression of genes regulating cardiac development, metabolism and function. Taken together these results reveal a critical role for MED1 in postnatal cardiac growth and development due to altered gene expression in adult cardiomyocytes.

scholarly journals Integration of multiple imaging platforms to uncover cardiac defects in adult zebrafish

2020 ◽  
Author(s):  
Anabela Bensimon-Brito ◽  
Giulia L. M. Boezio ◽  
João Cardeira-da-Silva ◽  
Astrid Wietelmann ◽  
Christian S. M. Helker ◽  
...  
Keyword(s):  
Cardiac Development ◽  
Genetic Model ◽  
Heart Function ◽  
Imaging Techniques ◽  
Adult Zebrafish ◽  
Micro Computed Tomography ◽  
Cardiac Defects ◽  
Multiple Parameters ◽  
Multiple Imaging ◽  
And Function

AbstractMammalian models have been instrumental to investigate adult heart function and human disease. However, electrophysiological differences with human hearts and high costs emphasize the need for additional models. The zebrafish is a well-established genetic model to study cardiac development and function; however, analysis of cardiac phenotypes in adult specimens is particularly challenging as they are opaque. Here, we optimized and combined multiple imaging techniques including echocardiography, magnetic resonance imaging and micro-computed tomography to identify and analyze cardiac phenotypes in adult zebrafish. Using alk5a/tgfbr1a mutants as a case study, we observed morphological and functional cardiac defects, which were undetected with conventional approaches. Correlation analysis of multiple parameters revealed an association between hemodynamic defects and structural alterations of the heart, as observed clinically. Thus, we report a comprehensive and sensitive platform to identify otherwise indiscernible cardiac phenotypes in adult zebrafish, a model with clear advantages to study cardiac function and disease.

scholarly journals Right Heart Structure, Geometry and Function Assessed by Echocardiography in 6-Year-Old Children Born Extremely Preterm—A Population-Based Cohort Study

2020 ◽  
Vol 10 (1) ◽  
pp. 122
Author(s):  
Lilly-Ann Mohlkert ◽  
Jenny Hallberg ◽  
Olof Broberg ◽  
Gunnar Sjöberg ◽  
Annika Rydberg ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Ductus Arteriosus ◽  
Population Based ◽  
Right Heart ◽  
Functional Changes ◽  
Cardiac Phenotype ◽  
Extremely Preterm ◽  
Healthy Control ◽  
The Right ◽  
And Function

Preterm birth has been associated with altered cardiac phenotype in adults. Our aim was to test the hypothesis that children surviving extremely preterm birth have important structural or functional changes of the right heart or pulmonary circulation. We also examined relations between birth size, gestational age, neonatal diagnoses of bronchopulmonary dysplasia (BPD) and patent ductus arteriosus (PDA) with cardiac outcomes. We assessed a population-based cohort of children born in Sweden before 27 weeks of gestation with echocardiography at 6.5 years of age (n = 176). Each preterm child was matched to a healthy control child born at term. Children born preterm had significantly smaller right atria, right ventricles with smaller widths, higher relative wall thickness and higher estimated pulmonary vascular resistance (PVR) than controls. In preterm children, PVR and right ventricular myocardial performance index (RVmpi’) were significantly higher in those with a PDA as neonates than in those without PDA, but no such associations were found with BPD. In conclusion, children born extremely preterm exhibit higher estimated PVR, altered right heart structure and function compared with children born at term.

Effects of avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice

2001 ◽  
Vol 281 (5) ◽  
pp. H1938-H1945 ◽  
Author(s):  
Chari Y. T. Hart ◽  
John C. Burnett ◽  
Margaret M. Redfield
Keyword(s):  
Cardiac Function ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Pressure Rise ◽  
Left Ventricular ◽  
Lv Function ◽  
Ketamine Anesthesia ◽  
The Difference ◽  
And Function ◽  
Derivatives Of

Anesthetic regimens commonly administered during studies that assess cardiac structure and function in mice are xylazine-ketamine (XK) and avertin (AV). While it is known that XK anesthesia produces more bradycardia in the mouse, the effects of XK and AV on cardiac function have not been compared. We anesthetized normal adult male Swiss Webster mice with XK or AV. Transthoracic echocardiography and closed-chest cardiac catheterization were performed to assess heart rate (HR), left ventricular (LV) dimensions at end diastole and end systole (LVDd and LVDs, respectively), fractional shortening (FS), LV end-diastolic pressure (LVEDP), the time constant of isovolumic relaxation (τ), and the first derivatives of LV pressure rise and fall (dP/d t max and dP/d t min, respectively). During echocardiography, HR was lower in XK than AV mice (250 ± 14 beats/min in XK vs. 453 ± 24 beats/min in AV, P < 0.05). Preload was increased in XK mice (LVDd: 4.1 ± 0.08 mm in XK vs. 3.8 ± 0.09 mm in AV, P < 0.05). FS, a load-dependent index of systolic function, was increased in XK mice (45 ± 1.2% in XK vs. 40 ± 0.8% in AV, P < 0.05). At LV catheterization, the difference in HR with AV (453 ± 24 beats/min) and XK (342 ± 30 beats/min, P < 0.05) anesthesia was more variable, and no significant differences in systolic or diastolic function were seen in the group as a whole. However, in XK mice with HR <300 beats/min, LVEDP was increased (28 ± 5 vs. 6.2 ± 2 mmHg in mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/d t max: 4,402 ± 798 vs. 8,250 ± 415 mmHg/s in mice with HR >300 beats/min, P < 0.05) and diastolic (τ: 23 ± 2 vs. 14 ± 1 ms in mice with HR >300 beats/min, P < 0.05) function were impaired. Compared with AV, XK produces profound bradycardia with effects on loading conditions and ventricular function. The disparate findings at echocardiography and LV catheterization underscore the importance of comprehensive assessment of LV function in the mouse.

Abstract 3: Il-10 Regulated Mir-375 Enhances Endothelial Progenitor Cell Mediated Myocardial Repair And Survival After Myocardial Infarction.

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Venkata N Garikipati ◽  
Prasanna Krishnamurthy ◽  
Suresh K Verma ◽  
Alexandra R Mackie ◽  
Erin E Vaughan ◽  
...  
Keyword(s):  
Capillary Density ◽  
Tube Formation ◽  
Lv Function ◽  
Myocardial Repair ◽  
Knock Down ◽  
Cardiac Functions ◽  
Dependent Protein ◽  
And Function ◽  
Deficient Mice

We hypothesized that IL-10 regulates miR-375 signaling in EPCs to enhance their survival and function in ischemic myocardium after MI. miR-375 knock down EPC were transplanted intramyocardially after induction of MI. Mice receiving EPC treated with miR-375 inhibitor showed increased number of GFP+EPCs retention that was associated with reduced EPC apoptosis in the myocardium. The engraftment of EPC into the vascular structures and the associated capillary density was significantly higher in miR-375-treated mice. The above findings further correlated with reduced infarct size, fibrosis and enhanced LV function (echocardiography) in miR-375 knock down EPC group as compared to scrambled EPC. Our in vitro studies revealed that the knockdown of miR-375 enhanced EPC proliferation, migration; tube formation ability and inhibited cell apoptosis, while the up-regulation of miR-375 with the mimic had the opposite effects. In addition, we found that miR-375 negatively regulates the expression of 3-phosphoinositide-dependent protein kinase 1 (PDK1) by directly targeting the 3'UTR of the PDK1 transcript. Interestingly, EPC isolated from IL-10-deficient mice has elevated basal levels of miR-375 and exhibited poor proliferation and tube formation ability where as miR-375 knock down in EPC isolated from IL-10 deficient mice attenuated these effects. Furthermore, transplantation of miR-375 knock down IL-10 deficient EPC after MI resulted in attenuated cardiac functions compared to scramble IL-10 deficient EPCs. Taken together, our studies suggest that IL-10 regulated miR-375 enhances EPC survival and function, associated with efficient myocardial repair via activation of PDK-1/AKT signaling cascades.

Abstract 47: Loss of the Cardio Protection Inferred by S-nitrosylation of GRK2 At Cysteine 340 Leads to Decreased Cardiac Performance and a Hypertensive Phenotype With Aging

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Christopher J Traynham ◽  
Ancai Yuan ◽  
Erhe Gao ◽  
Walter Koch
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Ischemia Reperfusion ◽  
Cardiac Performance ◽  
Heart Weight ◽  
Cardiac Phenotype ◽  
Cardio Protection ◽  
G Protein Coupled ◽  
Global Population

In the next 35 years, the global population of individuals above 60 years of age will double to approximately 2 billion. In the aged population, cardiovascular diseases are known to occur at a higher prevalence ultimately leading to increased mortality. G protein-coupled receptors (GPCRs) have been identified as vital regulators of cardiac function. GPCR kinases (GRKs) are important in cardiac GPCR regulation through desensitization of these receptors. GRK2 is highly expressed in the heart, and has been widely characterized due to its upregulation in heart failure. Studies from our lab have shown that elevated GRK2 levels in ischemia-reperfusion (I/R) injury result in a pro-death phenotype. Interestingly, cardio-protection can be inferred via S-nitrosylation of GRK2 at cysteine 340. Further, we have generated a knock-in GRK2 340S mouse, in which cysteine 340 was mutated to block dynamic GRK2 S-nitrosylation. GRK2 340S mice are more susceptible to I/R injury. Given that GRK2 340S mice are more susceptible to oxidative stress, and there is a nitroso-redox imbalance in senescence, it is possible that these mice are more likely to exhibit decreased cardiac performance as they age. Therefore, we hypothesize that with age GRK2 340S knockin mice will develop an overall worsened cardiac phenotype compared to control wild-type (WT) mice. To test this hypothesis, 340S and WT mice were aged for a year, and cardiac function was evaluated via echocardiography. Aged 340S mice exhibited significantly decreased ejection fraction and fraction shortening relative to aged WT controls. Prior to tissue harvesting, in-vivo hemodynamics was conducted via Millar catheterization. At baseline, aged 340S mice exhibited increased systolic blood pressure compared to aged WT mice. At the conclusion of this protocol, mice were sacrificed and heart weight (HW), body weight (BW), and tibia length (TL) measured to evaluate cardiac hypertrophy. Aged 340S mice exhibited significantly increased HW/BW and HW/TL ratios, indicative of cardiac hypertrophy, relative to aged WT controls. Taken together, these data suggest that with age, loss of the cardio protection inferred by S-nitrosylation of GRK2 at leads to decreased cardiac performance, and an overall worsened cardiac phenotype.

MIC-Drop: A platform for large-scale in vivo CRISPR screens

Science ◽  
2021 ◽  
pp. eabi8870
Author(s):  
Saba Parvez ◽  
Chelsea Herdman ◽  
Manu Beerens ◽  
Korak Chakraborti ◽  
Zachary P. Harmer ◽  
...  
Keyword(s):  
Large Scale ◽  
Cultured Cells ◽  
Cardiac Development ◽  
Droplet Microfluidics ◽  
Model Organisms ◽  
Genetic Screens ◽  
Large Numbers ◽  
And Function ◽  
Genome Scale

CRISPR-Cas9 can be scaled up for large-scale screens in cultured cells, but CRISPR screens in animals have been challenging because generating, validating, and keeping track of large numbers of mutant animals is prohibitive. Here, we report Multiplexed Intermixed CRISPR Droplets (MIC-Drop), a platform combining droplet microfluidics, single-needle en masse CRISPR ribonucleoprotein injections, and DNA barcoding to enable large-scale functional genetic screens in zebrafish. The platform can efficiently identify genes responsible for morphological or behavioral phenotypes. In one application, we show MIC-Drop can identify small molecule targets. Furthermore, in a MIC-Drop screen of 188 poorly characterized genes, we discover several genes important for cardiac development and function. With the potential to scale to thousands of genes, MIC-Drop enables genome-scale reverse-genetic screens in model organisms.

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.

Sign in / Sign up

Export Citation Format

Share Document