Rho Kinase Activity, Connexin 40, and Atrial Fibrillation: Mechanistic Insights from End-Stage Renal Disease on Dialysis Patients

Evidence on cellular/molecular mechanisms leading to atrial fibrillation (AF) are scanty. Increased expression of Rho kinase (ROCK) and myosin-phosphatase-target subunit-1 (MYPT-1), ROCK activity’s marker, were shown in AF patients, which correlated with connexin 40 (Cx40) expression, memb...

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Main Authors:	Lorenzo A. Calò, Verdiana Ravarotto, Giovanni Bertoldi, Elisa Pagnin, Barbara Rossi, Matteo Rigato, Paul A. Davis, Riccardo Proietti
Format:	Article
Language:	English
Published:	MDPI AG 2020-01-01
Series:	Journal of Clinical Medicine
Subjects:	atrial fibrillation rho kinase connexin cardiovascular–renal remodeling renal failure
Online Access:	https://www.mdpi.com/2077-0383/9/1/165

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spelling	doaj-d2307a0a587a4db2a4b58d57eac5a0d92020-11-25T01:32:46ZengMDPI AGJournal of Clinical Medicine2077-03832020-01-019116510.3390/jcm9010165jcm9010165Rho Kinase Activity, Connexin 40, and Atrial Fibrillation: Mechanistic Insights from End-Stage Renal Disease on Dialysis PatientsLorenzo A. Calò0Verdiana Ravarotto1Giovanni Bertoldi2Elisa Pagnin3Barbara Rossi4Matteo Rigato5Paul A. Davis6Riccardo Proietti7Department of Medicine, Nephrology, Dialysis and Transplantation Unit, University of Padova, 35128 Padova, ItalyDepartment of Medicine, Nephrology, Dialysis and Transplantation Unit, University of Padova, 35128 Padova, ItalyDepartment of Medicine, Nephrology, Dialysis and Transplantation Unit, University of Padova, 35128 Padova, ItalyDepartment of Medicine, Nephrology, Dialysis and Transplantation Unit, University of Padova, 35128 Padova, ItalyDepartment of Medicine, Nephrology, Dialysis and Transplantation Unit, University of Padova, 35128 Padova, ItalyDepartment of Medicine, Nephrology, Dialysis and Transplantation Unit, University of Padova, 35128 Padova, ItalyDepartment of Nutrition, University of California, Davis, CA 95616, USADepartment of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, ItalyEvidence on cellular/molecular mechanisms leading to atrial fibrillation (AF) are scanty. Increased expression of Rho kinase (ROCK) and myosin-phosphatase-target subunit-1 (MYPT-1), ROCK activity’s marker, were shown in AF patients, which correlated with connexin 40 (Cx40) expression, membrane protein of heart gap junctions, key for rapid action potential’s cell−cell transfer. AF is the most frequent arrhythmia in dialysis patients who present increased MYPT-1 phosphorylation, which correlates with left ventricular (LV) mass. Given ROCK’s established role in cardiovascular−renal remodeling, induction of impaired cell-to-cell coupling/potential conduction promoting AF initiation/perpetuation, we evaluated in dialysis patients with AF, MYPT-1 phosphorylation, Cx40 expression, and their relationships to support their involvement in AF. Mononuclear cells’ MYPT-1 phosphorylation, Cx40 expression, and the ROCK inhibitor fasudil’s effect were assessed in dialysis patients with AF (DPAFs), dialysis patients with sinus rhythm (DPs), and healthy subjects (C) (western blot). M-mode echocardiography assessed LV mass and left atrial systolic volume. DPAF’s phospho-MYPT-1 was increased vs. that of DPs and C (1.57 ± 0.17 d.u. vs. 0.69 ± 0.04 vs. 0.51 ± 0.05 respectively, <i>p</i> < 0.0001). DP’s phospho-MYPT-1 was higher vs. that of C, <i>p</i> = 0.009. DPAF’s Cx40 was higher vs. that of DPs and C (1.23 ± 0.12 vs. 0.74 ± 0.03 vs. 0.69 ± 0.03, <i>p</i> < 0.0001). DPAF’s phospho-MYPT-1 correlated with Cx40 (<i>p</i> < 0.001), left atrial systolic volume (<i>p</i> = 0.013), and LV mass (<i>p</i> = 0.014). In DPAFs, fasudil reduced MYPT-1 phosphorylation (<i>p</i> < 0.01) and Cx40 expression (<i>p</i> = 0.03). These data point toward ROCK and Cx40’s role in the mechanism(s) leading to AF in dialysis patients. Exploration of the ROCK pathway in AF could contribute to AF generation’s mechanistic explanations and likely identify potential pharmacologic targets for translation into treatment.https://www.mdpi.com/2077-0383/9/1/165atrial fibrillationrho kinaseconnexincardiovascular–renal remodelingrenal failure
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Lorenzo A. Calò Verdiana Ravarotto Giovanni Bertoldi Elisa Pagnin Barbara Rossi Matteo Rigato Paul A. Davis Riccardo Proietti
spellingShingle	Lorenzo A. Calò Verdiana Ravarotto Giovanni Bertoldi Elisa Pagnin Barbara Rossi Matteo Rigato Paul A. Davis Riccardo Proietti Rho Kinase Activity, Connexin 40, and Atrial Fibrillation: Mechanistic Insights from End-Stage Renal Disease on Dialysis Patients Journal of Clinical Medicine atrial fibrillation rho kinase connexin cardiovascular–renal remodeling renal failure
author_facet	Lorenzo A. Calò Verdiana Ravarotto Giovanni Bertoldi Elisa Pagnin Barbara Rossi Matteo Rigato Paul A. Davis Riccardo Proietti
author_sort	Lorenzo A. Calò
title	Rho Kinase Activity, Connexin 40, and Atrial Fibrillation: Mechanistic Insights from End-Stage Renal Disease on Dialysis Patients
title_short	Rho Kinase Activity, Connexin 40, and Atrial Fibrillation: Mechanistic Insights from End-Stage Renal Disease on Dialysis Patients
title_full	Rho Kinase Activity, Connexin 40, and Atrial Fibrillation: Mechanistic Insights from End-Stage Renal Disease on Dialysis Patients
title_fullStr	Rho Kinase Activity, Connexin 40, and Atrial Fibrillation: Mechanistic Insights from End-Stage Renal Disease on Dialysis Patients
title_full_unstemmed	Rho Kinase Activity, Connexin 40, and Atrial Fibrillation: Mechanistic Insights from End-Stage Renal Disease on Dialysis Patients
title_sort	rho kinase activity, connexin 40, and atrial fibrillation: mechanistic insights from end-stage renal disease on dialysis patients
publisher	MDPI AG
series	Journal of Clinical Medicine
issn	2077-0383
publishDate	2020-01-01
description	Evidence on cellular/molecular mechanisms leading to atrial fibrillation (AF) are scanty. Increased expression of Rho kinase (ROCK) and myosin-phosphatase-target subunit-1 (MYPT-1), ROCK activity’s marker, were shown in AF patients, which correlated with connexin 40 (Cx40) expression, membrane protein of heart gap junctions, key for rapid action potential’s cell−cell transfer. AF is the most frequent arrhythmia in dialysis patients who present increased MYPT-1 phosphorylation, which correlates with left ventricular (LV) mass. Given ROCK’s established role in cardiovascular−renal remodeling, induction of impaired cell-to-cell coupling/potential conduction promoting AF initiation/perpetuation, we evaluated in dialysis patients with AF, MYPT-1 phosphorylation, Cx40 expression, and their relationships to support their involvement in AF. Mononuclear cells’ MYPT-1 phosphorylation, Cx40 expression, and the ROCK inhibitor fasudil’s effect were assessed in dialysis patients with AF (DPAFs), dialysis patients with sinus rhythm (DPs), and healthy subjects (C) (western blot). M-mode echocardiography assessed LV mass and left atrial systolic volume. DPAF’s phospho-MYPT-1 was increased vs. that of DPs and C (1.57 ± 0.17 d.u. vs. 0.69 ± 0.04 vs. 0.51 ± 0.05 respectively, <i>p</i> < 0.0001). DP’s phospho-MYPT-1 was higher vs. that of C, <i>p</i> = 0.009. DPAF’s Cx40 was higher vs. that of DPs and C (1.23 ± 0.12 vs. 0.74 ± 0.03 vs. 0.69 ± 0.03, <i>p</i> < 0.0001). DPAF’s phospho-MYPT-1 correlated with Cx40 (<i>p</i> < 0.001), left atrial systolic volume (<i>p</i> = 0.013), and LV mass (<i>p</i> = 0.014). In DPAFs, fasudil reduced MYPT-1 phosphorylation (<i>p</i> < 0.01) and Cx40 expression (<i>p</i> = 0.03). These data point toward ROCK and Cx40’s role in the mechanism(s) leading to AF in dialysis patients. Exploration of the ROCK pathway in AF could contribute to AF generation’s mechanistic explanations and likely identify potential pharmacologic targets for translation into treatment.
topic	atrial fibrillation rho kinase connexin cardiovascular–renal remodeling renal failure
url	https://www.mdpi.com/2077-0383/9/1/165
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Rho Kinase Activity, Connexin 40, and Atrial Fibrillation: Mechanistic Insights from End-Stage Renal Disease on Dialysis Patients

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