Local hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats

Abstract Right ventricle (RV) dysfunction is an independent predictor of patient survival in heart failure (HF). However, the mechanisms of RV progression towards failing are not well understood. We studied cellular mechanisms of RV remodelling in a rat model of left ventricle myocardial infarction...

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Autores principales:	Roman Y. Medvedev, Jose L. Sanchez-Alonso, Catherine A. Mansfield, Aleksandra Judina, Alice J. Francis, Christina Pagiatakis, Natalia Trayanova, Alexey V. Glukhov, Michele Miragoli, Giuseppe Faggian, Julia Gorelik
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/81a2436481b242fbb548723b0ffe659f
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spelling	oai:doaj.org-article:81a2436481b242fbb548723b0ffe659f2021-12-02T13:30:51ZLocal hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats10.1038/s41598-021-84275-w2045-2322https://doaj.org/article/81a2436481b242fbb548723b0ffe659f2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84275-whttps://doaj.org/toc/2045-2322Abstract Right ventricle (RV) dysfunction is an independent predictor of patient survival in heart failure (HF). However, the mechanisms of RV progression towards failing are not well understood. We studied cellular mechanisms of RV remodelling in a rat model of left ventricle myocardial infarction (MI)-caused HF. RV myocytes from HF rats show significant cellular hypertrophy accompanied with a disruption of transverse-axial tubular network and surface flattening. Functionally these cells exhibit higher contractility with lower Ca2+ transients. The structural changes in HF RV myocytes correlate with more frequent spontaneous Ca2+ release activity than in control RV myocytes. This is accompanied by hyperactivated L-type Ca2+ channels (LTCCs) located specifically in the T-tubules of HF RV myocytes. The increased open probability of tubular LTCCs and Ca2+ sparks activation is linked to protein kinase A-mediated channel phosphorylation that occurs locally in T-tubules. Thus, our approach revealed that alterations in RV myocytes in heart failure are specifically localized in microdomains. Our findings may indicate the development of compensatory, though potentially arrhythmogenic, RV remodelling in the setting of LV failure. These data will foster better understanding of mechanisms of heart failure and it could promote an optimized treatment of patients.Roman Y. MedvedevJose L. Sanchez-AlonsoCatherine A. MansfieldAleksandra JudinaAlice J. FrancisChristina PagiatakisNatalia TrayanovaAlexey V. GlukhovMichele MiragoliGiuseppe FaggianJulia GorelikNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Roman Y. Medvedev Jose L. Sanchez-Alonso Catherine A. Mansfield Aleksandra Judina Alice J. Francis Christina Pagiatakis Natalia Trayanova Alexey V. Glukhov Michele Miragoli Giuseppe Faggian Julia Gorelik Local hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats
description	Abstract Right ventricle (RV) dysfunction is an independent predictor of patient survival in heart failure (HF). However, the mechanisms of RV progression towards failing are not well understood. We studied cellular mechanisms of RV remodelling in a rat model of left ventricle myocardial infarction (MI)-caused HF. RV myocytes from HF rats show significant cellular hypertrophy accompanied with a disruption of transverse-axial tubular network and surface flattening. Functionally these cells exhibit higher contractility with lower Ca2+ transients. The structural changes in HF RV myocytes correlate with more frequent spontaneous Ca2+ release activity than in control RV myocytes. This is accompanied by hyperactivated L-type Ca2+ channels (LTCCs) located specifically in the T-tubules of HF RV myocytes. The increased open probability of tubular LTCCs and Ca2+ sparks activation is linked to protein kinase A-mediated channel phosphorylation that occurs locally in T-tubules. Thus, our approach revealed that alterations in RV myocytes in heart failure are specifically localized in microdomains. Our findings may indicate the development of compensatory, though potentially arrhythmogenic, RV remodelling in the setting of LV failure. These data will foster better understanding of mechanisms of heart failure and it could promote an optimized treatment of patients.
format	article
author	Roman Y. Medvedev Jose L. Sanchez-Alonso Catherine A. Mansfield Aleksandra Judina Alice J. Francis Christina Pagiatakis Natalia Trayanova Alexey V. Glukhov Michele Miragoli Giuseppe Faggian Julia Gorelik
author_facet	Roman Y. Medvedev Jose L. Sanchez-Alonso Catherine A. Mansfield Aleksandra Judina Alice J. Francis Christina Pagiatakis Natalia Trayanova Alexey V. Glukhov Michele Miragoli Giuseppe Faggian Julia Gorelik
author_sort	Roman Y. Medvedev
title	Local hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats
title_short	Local hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats
title_full	Local hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats
title_fullStr	Local hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats
title_full_unstemmed	Local hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats
title_sort	local hyperactivation of l-type ca2+ channels increases spontaneous ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/81a2436481b242fbb548723b0ffe659f
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Local hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats

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