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Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation

BACKGROUND: Although aortic regurgitation (AR) is a clinically important condition that is becoming increasingly common, few relevant murine models and mechanistic studies exist for this condition. In this study, we attempted to delineate the pathological and molecular changes and address the roles...

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Autores principales: Wu, Jian, You, Jieyun, Wang, Xiaoyan, Wang, Shijun, Huang, Jiayuan, Xie, Qihai, Gong, Baoyong, Ding, Zhiwen, Ye, Yong, Wang, Cong, Kang, Le, Xu, Ran, Li, Yang, Chen, Ruizhen, Sun, Aijun, Yang, Xiangdong, Jiang, Hong, Yang, Fenghua, Backx, Peter H., Ge, Junbo, Zou, Yunzeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AME Publishing Company 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154424/
https://www.ncbi.nlm.nih.gov/pubmed/32309366
http://dx.doi.org/10.21037/atm.2020.01.51
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author Wu, Jian
You, Jieyun
Wang, Xiaoyan
Wang, Shijun
Huang, Jiayuan
Xie, Qihai
Gong, Baoyong
Ding, Zhiwen
Ye, Yong
Wang, Cong
Kang, Le
Xu, Ran
Li, Yang
Chen, Ruizhen
Sun, Aijun
Yang, Xiangdong
Jiang, Hong
Yang, Fenghua
Backx, Peter H.
Ge, Junbo
Zou, Yunzeng
author_facet Wu, Jian
You, Jieyun
Wang, Xiaoyan
Wang, Shijun
Huang, Jiayuan
Xie, Qihai
Gong, Baoyong
Ding, Zhiwen
Ye, Yong
Wang, Cong
Kang, Le
Xu, Ran
Li, Yang
Chen, Ruizhen
Sun, Aijun
Yang, Xiangdong
Jiang, Hong
Yang, Fenghua
Backx, Peter H.
Ge, Junbo
Zou, Yunzeng
author_sort Wu, Jian
collection PubMed
description BACKGROUND: Although aortic regurgitation (AR) is a clinically important condition that is becoming increasingly common, few relevant murine models and mechanistic studies exist for this condition. In this study, we attempted to delineate the pathological and molecular changes and address the roles of some potentially relevant molecules in an animal model of surgically induced AR. METHODS: AR was induced by puncturing the aortic valve leaflets in C57BL/6J mice under echocardiographic guidance. RESULTS: As early as 1 week following AR, the left ventricles (LV) displayed marked impairments in diastolic function and coronary flow reserve (CFR), as well as cardiac hypertrophy and chamber dilatation at both end-systole and end-diastole. LV free wall thickening and cardiomyocyte hypertrophy in LV were observed 2 weeks following of AR while a decline in ejection fraction was not seen until after 4 weeks. Nppa (natriuretic peptide A) and Nppb (natriuretic peptide B) increased over time, in conjunction with prominent Akt activation as well as slight CaMKII (Ca(2+)/calmodulin-dependent protein kinase II) activation and biphasic changes in β-arrestin-2 expression. Treatment of AR mice with Akt inhibition exacerbated the eccentric hypertrophy, while neither inhibition of CaMKII nor β-arrestin-2 overexpression influenced the response to AR. CONCLUSIONS: Our structural, functional, molecular and therapeutic analyses reveal that Akt, but not CaMKII or β-arrestin-2, plays a regulatory role in the development of LV remodeling after AR in Mice. These results may shed important light on therapeutic targets for volume overloaded cardiomyopathy.
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spelling pubmed-71544242020-04-17 Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation Wu, Jian You, Jieyun Wang, Xiaoyan Wang, Shijun Huang, Jiayuan Xie, Qihai Gong, Baoyong Ding, Zhiwen Ye, Yong Wang, Cong Kang, Le Xu, Ran Li, Yang Chen, Ruizhen Sun, Aijun Yang, Xiangdong Jiang, Hong Yang, Fenghua Backx, Peter H. Ge, Junbo Zou, Yunzeng Ann Transl Med Original Article BACKGROUND: Although aortic regurgitation (AR) is a clinically important condition that is becoming increasingly common, few relevant murine models and mechanistic studies exist for this condition. In this study, we attempted to delineate the pathological and molecular changes and address the roles of some potentially relevant molecules in an animal model of surgically induced AR. METHODS: AR was induced by puncturing the aortic valve leaflets in C57BL/6J mice under echocardiographic guidance. RESULTS: As early as 1 week following AR, the left ventricles (LV) displayed marked impairments in diastolic function and coronary flow reserve (CFR), as well as cardiac hypertrophy and chamber dilatation at both end-systole and end-diastole. LV free wall thickening and cardiomyocyte hypertrophy in LV were observed 2 weeks following of AR while a decline in ejection fraction was not seen until after 4 weeks. Nppa (natriuretic peptide A) and Nppb (natriuretic peptide B) increased over time, in conjunction with prominent Akt activation as well as slight CaMKII (Ca(2+)/calmodulin-dependent protein kinase II) activation and biphasic changes in β-arrestin-2 expression. Treatment of AR mice with Akt inhibition exacerbated the eccentric hypertrophy, while neither inhibition of CaMKII nor β-arrestin-2 overexpression influenced the response to AR. CONCLUSIONS: Our structural, functional, molecular and therapeutic analyses reveal that Akt, but not CaMKII or β-arrestin-2, plays a regulatory role in the development of LV remodeling after AR in Mice. These results may shed important light on therapeutic targets for volume overloaded cardiomyopathy. AME Publishing Company 2020-03 /pmc/articles/PMC7154424/ /pubmed/32309366 http://dx.doi.org/10.21037/atm.2020.01.51 Text en 2020 Annals of Translational Medicine. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Original Article
Wu, Jian
You, Jieyun
Wang, Xiaoyan
Wang, Shijun
Huang, Jiayuan
Xie, Qihai
Gong, Baoyong
Ding, Zhiwen
Ye, Yong
Wang, Cong
Kang, Le
Xu, Ran
Li, Yang
Chen, Ruizhen
Sun, Aijun
Yang, Xiangdong
Jiang, Hong
Yang, Fenghua
Backx, Peter H.
Ge, Junbo
Zou, Yunzeng
Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation
title Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation
title_full Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation
title_fullStr Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation
title_full_unstemmed Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation
title_short Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation
title_sort left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of akt, β-arrestin-2, and camkii in mice with aortic regurgitation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154424/
https://www.ncbi.nlm.nih.gov/pubmed/32309366
http://dx.doi.org/10.21037/atm.2020.01.51
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