scholarly journals Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

2019 ◽  
Author(s):  
Courtney E. Petersen ◽  
Matthew J. Wolf ◽  
Jeremy T. Smyth
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Heart Function ◽  
Animal Health ◽  
Normal Heart ◽  
Animal Cells ◽  
Functional Roles ◽  
Store Operated Calcium Entry ◽  
Heart Physiology ◽  
Fractional Shortening

ABSTRACTStore-operated Ca2+ entry (SOCE) is an essential Ca2+ signaling and homeostatic mechanism present in nearly all animal cells. SOCE refers to influx of Ca2+ into cells that is activated by depletion of endoplasmic or sarcoplasmic reticulum stores (ER/SR) Ca2+ stores. In the SOCE pathway, STIM proteins function as Ca2+ sensors in the ER, and upon ER Ca2+ store depletion STIM rearranges to ER-plasma membrane junctions where it activates Orai Ca2+ influx channels. Multiple studies have implicated STIM and Orai mediated SOCE in the pathogenesis of cardiac hypertrophy. Importantly however, the functional roles of SOCE in normal heart physiology have not been well defined. We have addressed this in Drosophila melanogaster, a powerful animal model of cardiac development and physiology. We show that heart specific suppression of Drosophila Stim and Orai resulted in reduced contractility consistent with dilated cardiomyopathy, characterized by increased end diastolic and end systolic dimensions and decreased fractional shortening. Reduced contractility was apparent in larval hearts and became more pronounced in adults. Myofibers were disorganized and more widely spaced in larval and adult hearts with Stim and Orai RNAi as compared to controls, possibly reflecting decompensation or upregulated stress response signaling due to altered Ca2+ homeostasis. Lastly, we show that reduced heart function significantly affected animal health and viability, as animals with heart specific Stim and Orai suppression exhibited significant delays in post-embryonic development and adults died significantly earlier than controls. Collectively, our results demonstrate that SOCE is essential for normal heart physiology and establish Drosophila as an important model for delineation of functional SOCE roles in cardiomyocytes.

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.

scholarly journals Mechanisms of TTNtv-Related Dilated Cardiomyopathy: Insights from Zebrafish Models

2021 ◽  
Vol 8 (2) ◽  
pp. 10
Author(s):  
Celine F. Santiago ◽  
Inken G. Huttner ◽  
Diane Fatkin
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Heart Function ◽  
Genetic Disorders ◽  
Zebrafish Model ◽  
Sarcomeric Protein ◽  
Treatment And Prevention ◽  
Muscle Disorder ◽  
Genetic And Environmental Factors ◽  
Sarcomere Assembly

Dilated cardiomyopathy (DCM) is a common heart muscle disorder characterized by ventricular dilation and contractile dysfunction that is associated with significant morbidity and mortality. New insights into disease mechanisms and strategies for treatment and prevention are urgently needed. Truncating variants in the TTN gene, which encodes the giant sarcomeric protein titin (TTNtv), are the most common genetic cause of DCM, but exactly how TTNtv promote cardiomyocyte dysfunction is not known. Although rodent models have been widely used to investigate titin biology, they have had limited utility for TTNtv-related DCM. In recent years, zebrafish (Danio rerio) have emerged as a powerful alternative model system for studying titin function in the healthy and diseased heart. Optically transparent embryonic zebrafish models have demonstrated key roles of titin in sarcomere assembly and cardiac development. The increasing availability of sophisticated imaging tools for assessment of heart function in adult zebrafish has revolutionized the field and opened new opportunities for modelling human genetic disorders. Genetically modified zebrafish that carry a human A-band TTNtv have now been generated and shown to spontaneously develop DCM with age. This zebrafish model will be a valuable resource for elucidating the phenotype modifying effects of genetic and environmental factors, and for exploring new drug therapies.

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.

Taurine-Deficient Dilated Cardiomyopathy in a Family of Golden Retrievers

2005 ◽  
Vol 41 (5) ◽  
pp. 284-291 ◽  
Author(s):  
Marie C. Bélanger ◽  
Mathieu Ouellet ◽  
Guillaume Queney ◽  
Maxim Moreau
Keyword(s):  
Dilated Cardiomyopathy ◽  
Systolic Function ◽  
Response To Therapy ◽  
Heart Murmur ◽  
Taurine Supplementation ◽  
Canine Dilated Cardiomyopathy ◽  
Fractional Shortening

A reversible taurine-deficient dilated cardiomyopathy occurred in five related golden retrievers. An apical systolic heart murmur was the most common physical abnormality. According to fractional shortening and end-systolic diameter on echocardiography, significant improvements (P<0.005) were recorded within 3 to 6 months of starting taurine supplementation. The dogs regained substantial systolic function, and four were weaned off all cardiac medications except taurine. This response to therapy was unusual, because canine dilated cardiomyopathy is generally progressive and fatal.

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.

Abstract 16592: Excessive MCU-Mediated Mitochondrial Calcium Uptake During Chronic Stress Impairs Cardiac Contractility

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Joanne F Garbincius ◽  
Timothy S Luongo ◽  
Jonathan P Lambert ◽  
Adam S Mangold ◽  
Emma K Murray ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Heart Function ◽  
Cardiac Contractility ◽  
Functional Adaptation ◽  
Lung Edema ◽  
Blue Dye ◽  
Contractile Dysfunction ◽  
Cyclophilin D ◽  
Fractional Shortening

Calcium (Ca 2+ ) uptake into the mitochondrial matrix occurs via the mitochondrial Ca 2+ uniporter channel (mtCU) and tunes mitochondrial metabolism to meet acute changes in cellular ATP demand. However, the role of mtCU-dependent mitochondrial Ca 2+ ( m Ca 2+ ) uptake in regulating homeostatic heart function and adaptation to chronic increases in workload remain controversial. We subjected mice with tamoxifen-inducible, cardiomyocyte-specific gain (flox-stop-MCU x αMHC-MCM, MCU-Tg) or loss ( Mcu fl/fl x αMHC-MCM , Mcu- cKO) of MCU function to 2wk isoproterenol (iso) infusion to test the hypothesis that m Ca 2+ uptake through MCU contributes to functional adaptation to sustained catecholamine signaling. Neither gain nor loss of MCU function altered baseline cardiac structure or function. Fractional shortening was increased after 2d of iso infusion in MCM control mice, but loss of MCU blocked this effect. In contrast, fractional shortening declined significantly after 7-14d of iso in MCU-Tg mice. MCU-Tg mice also exhibited increased LV dilation, heart mass, and lung edema compared to controls after 14d of iso. Acute treatment of MCU-Tg cardiomyocytes in vitro with the Ca 2+ ionophore ionomycin revealed increased ROS production and a trend towards increased sensitivity to Ca 2+ -induced cell death. In agreement, Evans blue dye exclusion assays revealed increased cardiomyocyte necrosis in MCU-Tg hearts following iso. Therefore, we deleted the mPTP regulator cyclophilin D (CypD) in MCU-Tg mice to test whether cardiomyocyte dropout due to m Ca 2+ overload-induced mPTP contributed to iso-induced contractile dysfunction. Unexpectedly, CypD deletion failed to attenuate contractile dysfunction and hypertrophic remodeling, and increased rather than attenuated iso-induced cardiomyocyte death in MCU-Tg mice. We conclude that while MCU-dependent m Ca 2+ uptake is required for the heart’s initial contractile response to catecholaminergic stress, under prolonged stimulation augmented m Ca 2+ uptake becomes deleterious and predisposes to cardiomyocyte death and heart failure. Our findings support the notion that the detrimental effects of sustained MCU-dependent m Ca 2+ uptake are mediated by mechanisms distinct from mitochondrial permeability transition.

Abstract 269: The Role of Neutrophils in Doxorubicin-induced Cardiotoxicity

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Anchit Bhagat ◽  
eugenie kleinerman ◽  
Eugenie Kleinerman
Keyword(s):  
Flow Cytometry ◽  
Ejection Fraction ◽  
Heart Function ◽  
Neutrophil Infiltration ◽  
Heart Tissue ◽  
Preventive Strategy ◽  
Neutrophil Depletion ◽  
Chemotherapy Agents ◽  
Fractional Shortening

Doxorubicin (Dox) is one of the most effective chemotherapy agents for treating childhood cancer. Unfortunately, Dox also causes damage to the heart which leads to reduced heart function and heart failure in >50% of survivors. Understanding the mechanisms by which Dox induces cardiotoxicity is crucial to identifying preventive interventions. Inflammation, in particular: neutrophils and monocytes has been linked to other form of cardiac disease. However, the role of these immune cells in Dox-induced cardiotoxicity has not been examined. We hypothesize that neutrophils are responsible for the early damage caused by Dox treatment. Using our mouse cardiotoxicity model, mice were treated with Doxorubicin for 2 weeks. Neutrophil infiltration in the heart 24 hours after therapy were evaluated by flow cytometry. There was an increase in neutrophils in heart tissue of Dox-treated mice as compared to controls and a decrease in heart function as quantified by echocardiography (ejection fraction [EF] and fractional shortening [FS]). Next, we depleted neutrophils using an anti-Ly6G antibody. Neutrophil depletion was confirmed by flow cytometry in the blood and hearts of Dox-treated mice. We found that neutrophil depletion prevented Dox-induced decrease in both ejection fraction and fractional shortening. Additionally, we also observed by flow cytometry that infiltration of monocytes was unaffected by the neutrophil depletion antibody. Based on this data we concluded that neutrophils and not monocytes are integral contributors to acute heart damage caused by Dox. These data indicate that targeting neutrophils may be a preventive strategy against Dox-induced cardiotoxicity.

scholarly journals Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

Biology Open ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. bio049999 ◽  
Author(s):  
Courtney E. Petersen ◽  
Matthew J. Wolf ◽  
Jeremy T. Smyth
Keyword(s):  
Dilated Cardiomyopathy ◽  
Calcium Entry ◽  
Store Operated Calcium Entry

1041Early changes in regional heart function in Tgalphaq*44 murine model of dilated cardiomyopathy as assessed by CMR Tagging

2013 ◽  
Vol 14 (suppl_1) ◽  
pp. i18-i18
Author(s):  
A Osiak ◽  
U Tyrankiewicz ◽  
M Jablonska ◽  
K Jasinski ◽  
PT Jochym ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Murine Model ◽  
Heart Function ◽  
Cmr Tagging
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