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Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy

Heart disease remains the number one killer of women in the US. Nonetheless, studies in women and female animal models continue to be underrepresented in cardiac research. Hypertrophic cardiomyopathy (HCM), the most commonly inherited cardiac disorder, has been tied to sarcomeric protein variants in...

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Autores principales: Dieseldorff Jones, Karissa M., Vied, Cynthia, Valera, Isela C., Chase, P. Bryant, Parvatiyar, Michelle S., Pinto, Jose R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081104/
https://www.ncbi.nlm.nih.gov/pubmed/32189431
http://dx.doi.org/10.14814/phy2.14396
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author Dieseldorff Jones, Karissa M.
Vied, Cynthia
Valera, Isela C.
Chase, P. Bryant
Parvatiyar, Michelle S.
Pinto, Jose R.
author_facet Dieseldorff Jones, Karissa M.
Vied, Cynthia
Valera, Isela C.
Chase, P. Bryant
Parvatiyar, Michelle S.
Pinto, Jose R.
author_sort Dieseldorff Jones, Karissa M.
collection PubMed
description Heart disease remains the number one killer of women in the US. Nonetheless, studies in women and female animal models continue to be underrepresented in cardiac research. Hypertrophic cardiomyopathy (HCM), the most commonly inherited cardiac disorder, has been tied to sarcomeric protein variants in both sexes. Among the susceptible genes, TNNC1—encoding cardiac troponin C (cTnC)—causes a substantial HCM phenotype in mice. Mice bearing an HCM‐associated cTnC‐A8V point mutation exhibited a significant decrease in stroke volume and left ventricular diameter and volume. Importantly, isovolumetric contraction time was significantly higher for female HCM mice. We utilized a transcriptomic approach to investigate the basis underlying the sexual dimorphism observed in the cardiac physiology of adult male and female HCM mice. RNA sequencing revealed several altered canonical pathways within the HCM mice versus WT groups including an increase in eukaryotic initiation factor 2 signaling, integrin‐linked kinase signaling, actin nucleation by actin‐related protein‐Wiskott‐Aldrich syndrome family protein complex, regulation of actin‐based motility by Rho kinase, vitamin D receptor/retinoid X receptor activation, and glutathione redox reaction pathways. In contrast, valine degradation, tricarboxylic acid cycle II, methionine degradation, and inositol phosphate compound pathways were notably down‐regulated in HCM mice. These down‐regulated pathways may be reduced in response to altered energetics in the hypertrophied hearts and may represent conservation of energy as the heart is compensating to meet increased contractile demands. HCM male versus female mice followed similar trends of the canonical pathways altered between HCM and WT. In addition, seven of the differentially expressed genes in both WT and HCM male versus female comparisons swapped directions in fold‐change between the sexes. These findings suggest a sexually‐dimorphic HCM phenotype due to a sarcomeric mutation and pinpoint several key targetable pathways and genes that may provide the means to alleviate the more severe decline in female cardiac function.
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spelling pubmed-70811042020-03-23 Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy Dieseldorff Jones, Karissa M. Vied, Cynthia Valera, Isela C. Chase, P. Bryant Parvatiyar, Michelle S. Pinto, Jose R. Physiol Rep Original Research Heart disease remains the number one killer of women in the US. Nonetheless, studies in women and female animal models continue to be underrepresented in cardiac research. Hypertrophic cardiomyopathy (HCM), the most commonly inherited cardiac disorder, has been tied to sarcomeric protein variants in both sexes. Among the susceptible genes, TNNC1—encoding cardiac troponin C (cTnC)—causes a substantial HCM phenotype in mice. Mice bearing an HCM‐associated cTnC‐A8V point mutation exhibited a significant decrease in stroke volume and left ventricular diameter and volume. Importantly, isovolumetric contraction time was significantly higher for female HCM mice. We utilized a transcriptomic approach to investigate the basis underlying the sexual dimorphism observed in the cardiac physiology of adult male and female HCM mice. RNA sequencing revealed several altered canonical pathways within the HCM mice versus WT groups including an increase in eukaryotic initiation factor 2 signaling, integrin‐linked kinase signaling, actin nucleation by actin‐related protein‐Wiskott‐Aldrich syndrome family protein complex, regulation of actin‐based motility by Rho kinase, vitamin D receptor/retinoid X receptor activation, and glutathione redox reaction pathways. In contrast, valine degradation, tricarboxylic acid cycle II, methionine degradation, and inositol phosphate compound pathways were notably down‐regulated in HCM mice. These down‐regulated pathways may be reduced in response to altered energetics in the hypertrophied hearts and may represent conservation of energy as the heart is compensating to meet increased contractile demands. HCM male versus female mice followed similar trends of the canonical pathways altered between HCM and WT. In addition, seven of the differentially expressed genes in both WT and HCM male versus female comparisons swapped directions in fold‐change between the sexes. These findings suggest a sexually‐dimorphic HCM phenotype due to a sarcomeric mutation and pinpoint several key targetable pathways and genes that may provide the means to alleviate the more severe decline in female cardiac function. John Wiley and Sons Inc. 2020-03-19 /pmc/articles/PMC7081104/ /pubmed/32189431 http://dx.doi.org/10.14814/phy2.14396 Text en © 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Dieseldorff Jones, Karissa M.
Vied, Cynthia
Valera, Isela C.
Chase, P. Bryant
Parvatiyar, Michelle S.
Pinto, Jose R.
Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy
title Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy
title_full Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy
title_fullStr Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy
title_full_unstemmed Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy
title_short Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy
title_sort sexual dimorphism in cardiac transcriptome associated with a troponin c murine model of hypertrophic cardiomyopathy
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081104/
https://www.ncbi.nlm.nih.gov/pubmed/32189431
http://dx.doi.org/10.14814/phy2.14396
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