scholarly journals Disrupted mechanobiology links the molecular and cellular phenotypes in familial dilated cardiomyopathy

2019 ◽  
Vol 116 (36) ◽  
pp. 17831-17840 ◽  
Author(s):  
Sarah R. Clippinger ◽  
Paige E. Cloonan ◽  
Lina Greenberg ◽  
Melanie Ernst ◽  
W. Tom Stump ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Troponin T ◽  
Heart Tissue ◽  
Substrate Stiffness ◽  
Cellular Organization ◽  
Sarcomeric Proteins ◽  
Critical Gap ◽  
Cellular Hypertrophy ◽  
Familial Dilated Cardiomyopathy ◽  
Cellular Phenotypes

Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a major indicator for heart transplant. The disease is frequently caused by mutations of sarcomeric proteins; however, it is not well understood how these molecular mutations lead to alterations in cellular organization and contractility. To address this critical gap in our knowledge, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, ΔK210. We determined the molecular mechanism of ΔK210 and used computational modeling to predict that the mutation should reduce the force per sarcomere. In mutant cardiomyocytes, we found that ΔK210 not only reduces contractility but also causes cellular hypertrophy and impairs cardiomyocytes’ ability to adapt to changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and disease). These results help link the molecular and cellular phenotypes and implicate alterations in mechanosensing as an important factor in the development of DCM.

scholarly journals Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes in Familial Dilated Cardiomyopathy

2019 ◽  
Author(s):  
Sarah R. Clippinger ◽  
Paige E. Cloonan ◽  
Lina Greenberg ◽  
Melanie Ernst ◽  
W. Tom Stump ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Troponin T ◽  
Heart Tissue ◽  
Substrate Stiffness ◽  
Cellular Organization ◽  
Sarcomeric Proteins ◽  
Critical Gap ◽  
Cellular Hypertrophy ◽  
Familial Dilated Cardiomyopathy ◽  
Cellular Phenotypes

AbstractFamilial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a major indicator for heart transplant. The disease is frequently caused by mutations of sarcomeric proteins; however, it is not well understood how these molecular mutations lead to alterations in cellular organization and contractility. To address this critical gap in our knowledge, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, ΔK210. We determined the molecular mechanism of ΔK210 and used computational modeling to predict that the mutation should reduce the force per sarcomere. In mutant cardiomyocytes, we found that ΔK210 not only reduces contractility, but also causes cellular hypertrophy and impairs cardiomyocytes’ ability to adapt to changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and disease). These results link the molecular and cellular phenotypes and implicate alterations in mechanosensing as an important factor in the development of DCM.

Abstract 904: Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes in Familial Dilated Cardiomyopathy

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Michael J Greenberg ◽  
Sarah R Clippinger ◽  
Paige E Cloonan ◽  
Melanie Ernst ◽  
Tom Stump ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Familial Dilated Cardiomyopathy ◽  
Cellular Phenotypes

scholarly journals GSK-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy

2016 ◽  
Vol 310 (11) ◽  
pp. H1808-H1815 ◽  
Author(s):  
Rasha M. S. M. Mohamed ◽  
Sachio Morimoto ◽  
Islam A. A. E.-H. Ibrahim ◽  
Dong-Yun Zhan ◽  
Cheng-Kun Du ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dilated Cardiomyopathy ◽  
Glycogen Synthase ◽  
Troponin T ◽  
Systolic Function ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Myosin Heavy Chain Isoform ◽  
Familial Dilated Cardiomyopathy ◽  
Gsk 3Β

Glycogen synthase kinase-3β (GSK-3β) plays a central role in both cardiac physiology and pathology. Herein we want to clarify the role of GSK-3β in familial dilated cardiomyopathy. We generated a mouse model carrying a heterozygous knockout mutation of GSK-3β (GSK-3β+/− KO), together with a ΔK210 knockin mutation in cardiac troponin T (ΔK210 cTnT KI), which was proved to be one of the genetic causes of familial dilated cardiomyopathy (DCM). GSK-3β+/− KO prevented the slow and rapid deterioration in left ventricular systolic function accompanying heart failure (HF) in DCM mice with heterozygous and homozygous ΔK210 cTnT KI mutations, respectively. GSK-3β+/− KO also prevented cardiac enlargement, myocardial fibrosis, and cardiomyocyte apoptosis and markedly reduced the expression of cardiac β-myosin heavy chain isoform, indicative of HF, in DCM mice with homozygous ΔK210 cTnT KI mutation. GSK-3β+/− KO also extended the life span of these DCM mice. This study suggests that the inhibition of GSK-3β is cardioprotective in familial DCM associated with ΔK210 cTnT mutation.

scholarly journals Whole Exome Sequencing Identifies a Troponin T Mutation Hot Spot in Familial Dilated Cardiomyopathy

PLoS ONE ◽  
2013 ◽  
Vol 8 (10) ◽  
pp. e78104 ◽  
Author(s):  
Nzali Campbell ◽  
Gianfranco Sinagra ◽  
Kenneth L. Jones ◽  
Dobromir Slavov ◽  
Katherine Gowan ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Troponin T ◽  
Hot Spot ◽  
Familial Dilated Cardiomyopathy ◽  
Whole Exome

Abstract 10260: Thrombin is a Novel Target of the Treatment of Dilated Cardiomyopathy

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Keiichi Ito ◽  
Kenichi Hongo ◽  
Taro Date ◽  
Yusuke Kashiwagi ◽  
Takuya Yoshino ◽  
...  
Keyword(s):  
Heart Disease ◽  
Dilated Cardiomyopathy ◽  
Troponin T ◽  
Immunohistochemical Analysis ◽  
Heart Tissue ◽  
Left Ventricular ◽  
Apoptotic Index ◽  
Direct Thrombin Inhibitor ◽  
Thrombin Inhibitor ◽  
Thrombin Inhibition

Introduction: A state of hypercoagulability has been observed in patients with dilated cardiomyopathy (DCM) compared to healthy subjects. In addition to being found in blood, thrombin is also expressed in the heart. Hypothesis: We hypothesize that thrombin in the heart tissue may contribute to the pathology of DCM and thrombin inhibition may be beneficial for the development of DCM. Methods: We evaluated the expression of thrombin by immunohistochemical analysis in the left ventricle of 5 patients with DCM undergoing Batista operation and that of 4 patients without heart disease serving as controls. The immunohistochemical staining was scored subjectively on a semi-quantitative scale of 0-4. We investigated the effects of the direct thrombin inhibitor, dabigatran, in the development of DCM in a mouse model carrying a deletion mutant of cardiac troponin T (DCM mouse) which causes human DCM, by using echocardiography and Kaplan-Meier method. We also estimated the apoptotic index using the terminal dUTP nick-end labeling (TUNEL) assay using the heart tissue from DCM mouse. Results: Immunohistochemical analysis showed strong thrombin expression in DCM patients compared to patients without heart disease [3.60 in DCM (n=5), 1.25 in control (n=4), p<0.001]. Dabigatran significantly improved impaired left ventricular function of DCM mouse by echocardiographic examination; fractional shortening was 15.6±5.7 % in DCM mouse and was 42.7±7.3 % in DCM with dabigatran (p=0.03, n=4). Dabigatran also significantly improved the poor outcome of DCM mouse (p=0.02, n=7) (Figure1). Although there were no significant differences, dabigatran tended to reduce the apoptotic index; the percentage of TUNEL-positive nuclei was 0.20±0.04 % in DCM mouse and was 0.08±0.05 % in DCM with dabigatran (p=0.11, n=4). Conclusion: Upregulation of tissue thrombin may be involved in the pathogenesis of DCM. The direct thrombin inhibitor, dabigatran, may be a possible treatment option against DCM.

Novel troponin T mutation in familial dilated cardiomyopathy with gender-dependant severity

2004 ◽  
Vol 83 (1-2) ◽  
pp. 188-196 ◽  
Author(s):  
Christopher B. Stefanelli ◽  
Amnon Rosenthal ◽  
Andrei B. Borisov ◽  
Gregory J. Ensing ◽  
Mark W. Russell
Keyword(s):  
Dilated Cardiomyopathy ◽  
Troponin T ◽  
Familial Dilated Cardiomyopathy

scholarly journals Novel Cardiac Troponin T Mutation as a Cause of Familial Dilated Cardiomyopathy

Circulation ◽  
2001 ◽  
Vol 104 (18) ◽  
pp. 2188-2193 ◽  
Author(s):  
Duanxiang Li ◽  
Grazyna Z. Czernuszewicz ◽  
Oscar Gonzalez ◽  
Terry Tapscott ◽  
Akihiko Karibe ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Troponin ◽  
Troponin T ◽  
Cardiac Troponin T ◽  
Familial Dilated Cardiomyopathy

scholarly journals WHOLE EXOME SEQUENCING IDENTIFIES A TROPONIN T MUTATION HOT SPOT IN FAMILIAL DILATED CARDIOMYOPATHY

2013 ◽  
Vol 61 (10) ◽  
pp. E594
Author(s):  
Luisa Mestroni ◽  
Nzali Campbell ◽  
Gianfranco Sinagra ◽  
Kenneth Jones ◽  
Dobromir Slavov ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Troponin T ◽  
Hot Spot ◽  
Familial Dilated Cardiomyopathy ◽  
Whole Exome

Abstract P439: Harnessing Multiscale Models Of A Dilated Cardiomyopathy Mutation For Precision Medicine

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Lina Greenberg ◽  
W. Tom Stump ◽  
Andrea L Bredemeyer ◽  
Kory J Lavine ◽  
Michael J Greenberg
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Precision Medicine ◽  
Thin Filament ◽  
Troponin T ◽  
Molecular Complexes ◽  
Multiscale Approach ◽  
Familial Dilated Cardiomyopathy ◽  
Omecamtiv Mecarbil ◽  
Human Mutation

Familial dilated cardiomyopathy (DCM) is a leading cause of both adult and pediatric heart failure. Currently, there is no cure for DCM, and the 5-year transplant free survival rate is <50%. There is therefore an outstanding need to develop new therapeutics. Prior studies have established a strong genetic basis for DCM and identified causative genetic mutations. These observations provide unique opportunities to apply precision medicine approaches that target and circumvent the effects of deleterious mutations. Here, we used a multiscale approach to study the consequences of a human mutation in troponin T that causes DCM, ΔK210. We found that at the molecular scale ΔK210 changes the positioning of tropomyosin along the thin filament, leading to molecular hypocontractility. Using genome edited human stem cell derived cardiomyocytes heterozygous for the mutation, we show reduced cellular contractility at the single cell and tissue levels. Importantly, we demonstrate that mutant tissues show a reduced Frank-Starling response, increased stiffness, and misaligned myocytes. Based on our molecular mechanism, we hypothesized that treatment of ΔK210 with Omecamtiv Mecarbil (OM), a thin filament activator in clinical trials for heart failure, would improve the function of mutant tissues. We found that treatment of ΔK210 molecular complexes and tissues with OM causes a dose-dependent increase in cardiac function, reversing the mutation-induced contractile defect. Taken together, our study demonstrates how mechanistic molecular studies can be harnessed to identify precision medicine therapeutics.

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