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Recovery of left ventricular function following in vivo reexpression of cardiac myosin binding protein C

The loss of cardiac myosin binding protein C (cMyBP-C) results in left ventricular dilation, cardiac hypertrophy, and impaired ventricular function in both constitutive and conditional cMyBP-C knockout (MYBPC3 null) mice. It remains unclear whether the structural and functional phenotypes expressed...

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Autores principales: Giles, Jasmine, Patel, Jitandrakumar R., Miller, Adam, Iverson, Elizabeth, Fitzsimons, Daniel, Moss, Richard L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314388/
https://www.ncbi.nlm.nih.gov/pubmed/30573635
http://dx.doi.org/10.1085/jgp.201812238
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author Giles, Jasmine
Patel, Jitandrakumar R.
Miller, Adam
Iverson, Elizabeth
Fitzsimons, Daniel
Moss, Richard L.
author_facet Giles, Jasmine
Patel, Jitandrakumar R.
Miller, Adam
Iverson, Elizabeth
Fitzsimons, Daniel
Moss, Richard L.
author_sort Giles, Jasmine
collection PubMed
description The loss of cardiac myosin binding protein C (cMyBP-C) results in left ventricular dilation, cardiac hypertrophy, and impaired ventricular function in both constitutive and conditional cMyBP-C knockout (MYBPC3 null) mice. It remains unclear whether the structural and functional phenotypes expressed in the MYBPC3 null mouse are reversible, which is an important question, since reduced expression of cMyBP-C is an important cause of hypertrophic cardiomyopathy in humans. To investigate this question, we generated a cardiac-specific transgenic mouse model using a Tet-Off inducible system to permit the controlled expression of WT cMyBP-C on the MYBPC3 null background. Functional Tet-Off mice expressing WT cMyBP-C (FT-WT) were generated by crossing tetracycline transactivator mice with responder mice carrying the WT cMyBP-C transgene. Prior to dietary doxycycline administration, cMyBP-C was expressed at normal levels in FT-WT myocardium, which exhibited similar levels of steady-state force and in vivo left ventricular function as WT mice. Introduction of dietary doxycycline for four weeks resulted in a partial knockdown of cMyBP-C expression and commensurate impairment of systolic and diastolic function to levels approaching those observed in MYBPC 3 null mice. Subsequent withdrawal of doxycycline from the diet resulted in the reexpression of cMyBP-C to levels comparable to those observed in WT mice, along with near-complete recovery of in vivo ventricular function. These results show that the cardiac phenotypes associated with MYBPC3 null mice are reversible. Our work also validates the use of the Tet-Off inducible system as a means to study the mechanisms underlying hypertrophic cardiomyopathy.
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spelling pubmed-63143882019-07-07 Recovery of left ventricular function following in vivo reexpression of cardiac myosin binding protein C Giles, Jasmine Patel, Jitandrakumar R. Miller, Adam Iverson, Elizabeth Fitzsimons, Daniel Moss, Richard L. J Gen Physiol Research Articles The loss of cardiac myosin binding protein C (cMyBP-C) results in left ventricular dilation, cardiac hypertrophy, and impaired ventricular function in both constitutive and conditional cMyBP-C knockout (MYBPC3 null) mice. It remains unclear whether the structural and functional phenotypes expressed in the MYBPC3 null mouse are reversible, which is an important question, since reduced expression of cMyBP-C is an important cause of hypertrophic cardiomyopathy in humans. To investigate this question, we generated a cardiac-specific transgenic mouse model using a Tet-Off inducible system to permit the controlled expression of WT cMyBP-C on the MYBPC3 null background. Functional Tet-Off mice expressing WT cMyBP-C (FT-WT) were generated by crossing tetracycline transactivator mice with responder mice carrying the WT cMyBP-C transgene. Prior to dietary doxycycline administration, cMyBP-C was expressed at normal levels in FT-WT myocardium, which exhibited similar levels of steady-state force and in vivo left ventricular function as WT mice. Introduction of dietary doxycycline for four weeks resulted in a partial knockdown of cMyBP-C expression and commensurate impairment of systolic and diastolic function to levels approaching those observed in MYBPC 3 null mice. Subsequent withdrawal of doxycycline from the diet resulted in the reexpression of cMyBP-C to levels comparable to those observed in WT mice, along with near-complete recovery of in vivo ventricular function. These results show that the cardiac phenotypes associated with MYBPC3 null mice are reversible. Our work also validates the use of the Tet-Off inducible system as a means to study the mechanisms underlying hypertrophic cardiomyopathy. Rockefeller University Press 2019-01-07 /pmc/articles/PMC6314388/ /pubmed/30573635 http://dx.doi.org/10.1085/jgp.201812238 Text en © 2018 Giles et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Giles, Jasmine
Patel, Jitandrakumar R.
Miller, Adam
Iverson, Elizabeth
Fitzsimons, Daniel
Moss, Richard L.
Recovery of left ventricular function following in vivo reexpression of cardiac myosin binding protein C
title Recovery of left ventricular function following in vivo reexpression of cardiac myosin binding protein C
title_full Recovery of left ventricular function following in vivo reexpression of cardiac myosin binding protein C
title_fullStr Recovery of left ventricular function following in vivo reexpression of cardiac myosin binding protein C
title_full_unstemmed Recovery of left ventricular function following in vivo reexpression of cardiac myosin binding protein C
title_short Recovery of left ventricular function following in vivo reexpression of cardiac myosin binding protein C
title_sort recovery of left ventricular function following in vivo reexpression of cardiac myosin binding protein c
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314388/
https://www.ncbi.nlm.nih.gov/pubmed/30573635
http://dx.doi.org/10.1085/jgp.201812238
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