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Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype

Heart failure (HF) with preserved ejection fraction (HFpEF) is defined as HF with an ejection fraction (EF) ≥ 50% and elevated cardiac diastolic filling pressures. The underlying causes of HFpEF are multifactorial and not well-defined. A transgenic mouse with low levels of cardiomyocyte (CM)-specifi...

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Autores principales: Li, Yijia, Kubo, Hajime, Yu, Daohai, Yang, Yijun, Johnson, Jaslyn P., Eaton, Deborah M., Berretta, Remus M., Foster, Michael, McKinsey, Timothy A., Yu, Jun, Elrod, John W., Chen, Xiongwen, Houser, Steven R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Physiological Society 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9988529/
https://www.ncbi.nlm.nih.gov/pubmed/36763506
http://dx.doi.org/10.1152/ajpheart.00594.2022
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author Li, Yijia
Kubo, Hajime
Yu, Daohai
Yang, Yijun
Johnson, Jaslyn P.
Eaton, Deborah M.
Berretta, Remus M.
Foster, Michael
McKinsey, Timothy A.
Yu, Jun
Elrod, John W.
Chen, Xiongwen
Houser, Steven R.
author_facet Li, Yijia
Kubo, Hajime
Yu, Daohai
Yang, Yijun
Johnson, Jaslyn P.
Eaton, Deborah M.
Berretta, Remus M.
Foster, Michael
McKinsey, Timothy A.
Yu, Jun
Elrod, John W.
Chen, Xiongwen
Houser, Steven R.
author_sort Li, Yijia
collection PubMed
description Heart failure (HF) with preserved ejection fraction (HFpEF) is defined as HF with an ejection fraction (EF) ≥ 50% and elevated cardiac diastolic filling pressures. The underlying causes of HFpEF are multifactorial and not well-defined. A transgenic mouse with low levels of cardiomyocyte (CM)-specific inducible Cavβ2a expression (β2a-Tg mice) showed increased cytosolic CM Ca(2+), and modest levels of CM hypertrophy, and fibrosis. This study aimed to determine if β2a-Tg mice develop an HFpEF phenotype when challenged with two additional stressors, high-fat diet (HFD) and N(ω)-nitro-l-arginine methyl ester (l-NAME, LN). Four-month-old wild-type (WT) and β2a-Tg mice were given either normal chow (WT-N, β2a-N) or HFD and/or l-NAME (WT-HFD, WT-LN, WT-HFD-LN, β2a-HFD, β2a-LN, and β2a-HFD-LN). Some animals were treated with the histone deacetylase (HDAC) (hypertrophy regulators) inhibitor suberoylanilide hydroxamic acid (SAHA) (β2a-HFD-LN-SAHA). Echocardiography was performed monthly. After 4 mo of treatment, terminal studies were performed including invasive hemodynamics and organs weight measurements. Cardiac tissue was collected. Four months of HFD plus l-NAME treatment did not induce a profound HFpEF phenotype in FVB WT mice. β2a-HFD-LN (3-Hit) mice developed features of HFpEF, including increased atrial natriuretic peptide (ANP) levels, preserved EF, diastolic dysfunction, robust CM hypertrophy, increased M(2)-macrophage population, and myocardial fibrosis. SAHA reduced the HFpEF phenotype in the 3-Hit mouse model, by attenuating these effects. The 3-Hit mouse model induced a reliable HFpEF phenotype with CM hypertrophy, cardiac fibrosis, and increased M(2)-macrophage population. This model could be used for identifying and preclinical testing of novel therapeutic strategies. NEW & NOTEWORTHY Our study shows that three independent pathological stressors (increased Ca(2+) influx, high-fat diet, and l-NAME) together produce a profound HFpEF phenotype. The primary mechanisms include HDAC-dependent-CM hypertrophy, necrosis, increased M(2)-macrophage population, fibroblast activation, and myocardial fibrosis. A role for HDAC activation in the HFpEF phenotype was shown in studies with SAHA treatment, which prevented the severe HFpEF phenotype. This “3-Hit” mouse model could be helpful in identifying novel therapeutic strategies to treat HFpEF.
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spelling pubmed-99885292023-03-08 Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype Li, Yijia Kubo, Hajime Yu, Daohai Yang, Yijun Johnson, Jaslyn P. Eaton, Deborah M. Berretta, Remus M. Foster, Michael McKinsey, Timothy A. Yu, Jun Elrod, John W. Chen, Xiongwen Houser, Steven R. Am J Physiol Heart Circ Physiol Research Article Heart failure (HF) with preserved ejection fraction (HFpEF) is defined as HF with an ejection fraction (EF) ≥ 50% and elevated cardiac diastolic filling pressures. The underlying causes of HFpEF are multifactorial and not well-defined. A transgenic mouse with low levels of cardiomyocyte (CM)-specific inducible Cavβ2a expression (β2a-Tg mice) showed increased cytosolic CM Ca(2+), and modest levels of CM hypertrophy, and fibrosis. This study aimed to determine if β2a-Tg mice develop an HFpEF phenotype when challenged with two additional stressors, high-fat diet (HFD) and N(ω)-nitro-l-arginine methyl ester (l-NAME, LN). Four-month-old wild-type (WT) and β2a-Tg mice were given either normal chow (WT-N, β2a-N) or HFD and/or l-NAME (WT-HFD, WT-LN, WT-HFD-LN, β2a-HFD, β2a-LN, and β2a-HFD-LN). Some animals were treated with the histone deacetylase (HDAC) (hypertrophy regulators) inhibitor suberoylanilide hydroxamic acid (SAHA) (β2a-HFD-LN-SAHA). Echocardiography was performed monthly. After 4 mo of treatment, terminal studies were performed including invasive hemodynamics and organs weight measurements. Cardiac tissue was collected. Four months of HFD plus l-NAME treatment did not induce a profound HFpEF phenotype in FVB WT mice. β2a-HFD-LN (3-Hit) mice developed features of HFpEF, including increased atrial natriuretic peptide (ANP) levels, preserved EF, diastolic dysfunction, robust CM hypertrophy, increased M(2)-macrophage population, and myocardial fibrosis. SAHA reduced the HFpEF phenotype in the 3-Hit mouse model, by attenuating these effects. The 3-Hit mouse model induced a reliable HFpEF phenotype with CM hypertrophy, cardiac fibrosis, and increased M(2)-macrophage population. This model could be used for identifying and preclinical testing of novel therapeutic strategies. NEW & NOTEWORTHY Our study shows that three independent pathological stressors (increased Ca(2+) influx, high-fat diet, and l-NAME) together produce a profound HFpEF phenotype. The primary mechanisms include HDAC-dependent-CM hypertrophy, necrosis, increased M(2)-macrophage population, fibroblast activation, and myocardial fibrosis. A role for HDAC activation in the HFpEF phenotype was shown in studies with SAHA treatment, which prevented the severe HFpEF phenotype. This “3-Hit” mouse model could be helpful in identifying novel therapeutic strategies to treat HFpEF. American Physiological Society 2023-04-01 2023-02-10 /pmc/articles/PMC9988529/ /pubmed/36763506 http://dx.doi.org/10.1152/ajpheart.00594.2022 Text en Copyright © 2023 The Authors. https://creativecommons.org/licenses/by/4.0/Licensed under Creative Commons Attribution CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/) . Published by the American Physiological Society.
spellingShingle Research Article
Li, Yijia
Kubo, Hajime
Yu, Daohai
Yang, Yijun
Johnson, Jaslyn P.
Eaton, Deborah M.
Berretta, Remus M.
Foster, Michael
McKinsey, Timothy A.
Yu, Jun
Elrod, John W.
Chen, Xiongwen
Houser, Steven R.
Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype
title Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype
title_full Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype
title_fullStr Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype
title_full_unstemmed Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype
title_short Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype
title_sort combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9988529/
https://www.ncbi.nlm.nih.gov/pubmed/36763506
http://dx.doi.org/10.1152/ajpheart.00594.2022
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