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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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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. |
format | Online Article Text |
id | pubmed-7081104 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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