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

Abstract

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, p < 0.0001). DP’s phospho-MYPT-1 was higher vs. that of C, p = 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, p < 0.0001). DPAF’s phospho-MYPT-1 correlated with Cx40 (p < 0.001), left atrial systolic volume (p = 0.013), and LV mass (p = 0.014). In DPAFs, fasudil reduced MYPT-1 phosphorylation (p < 0.01) and Cx40 expression (p = 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.

The Pivotal Role of Oxidative Stress in the Pathophysiology of Cardiovascular-Renal Remodeling in Kidney Disease

“…Our recent study in dialysis patients demonstrated that patients with atrial fibrillation, contrarily to those dialysis patients with no atrial fibrillation, had increased ROCK activity in terms of MYPT-1 phosphorylation which correlates positively with increased Cx40 level. In addition, the incubation of peripheral mononuclear cells of these patients with the ROCK inhibitor fasudil reduced Cx40 protein expression supporting the hypothesis that Cx40 may be a downstream target of RhoA/ROCK pathway [70]. These results add therefore additional evidences for the involvement of RhoA/ROCK pathway in the perpetuation of atrial fibrillation, also in the light of the role of MAPK in theregulation of Cxs expression [71].…”

Oxidants and Cardiorenal Vascular Remodeling—Insights from Rare Genetic Tubulopathies: Bartter’s and Gitelman’s Syndromes

“…There are multiple mechanisms through which ROS can potentially stimulate AF, by causing increased ion leak throughout mycardiocytes [ 26 ], as well as by stimulating collagen deposition and fibrosis that interferes with the propagation of the electric impulse [ 29 ]. Ang II increases Rho kinase (ROCK) activity, leading to elevated myosin phosphatase target protein subunit-1 (MYPT-1) phosphorylation, and to the increased expression of Connexin 40, an integral membrane protein of heart gap cells junction, which enhances atrial vulnerability to electrical disturbances [ 30 , 31 ].…”

Pathomechanism of oxidative stress in cardiovascularrenal remodeling and therapeutic strategies

“…In studies of patients undergoing chronic dialysis, an interesting link between ROCK activity and cardiac electrical disturbances, as assessed by the relationship between MYPT-1 phosphorylation and connexin 40 (Cx40) expres- www.krcp-ksn.org sion, has been reported [44,49]. As an integral membrane protein of heart cell gap junctions, Cx40 is fundamental for rapid cell-cell transfer of action potentials, and increased expression of Cx40 enhances the vulnerability of the atrial myocardium to atrial fibrillation [50].…”

“…We reported that patients undergoing dialysis with permanent atrial fibrillation display increased Cx40 expression compared to dialysis patients without atrial fibrillation as well as increased MYPT-1 phosphorylation. This latter in atrial fibrillation patients also correlated with Cx40, with left atrial systolic volume, and with cardiac mass [ 49 ].…”