Increased rho kinase activity in mononuclear cells of dialysis and stage 3–4 chronic kidney disease patients with left ventricular hypertrophy: Cardiovascular risk implications

Calò, Lorenzo A.; Vertolli, Ugo; Pagnin, Elisa; Ravarotto, Verdiana; Davis, Paul A.; Lupia, M; Naso, Elena; Maiolino, Giuseppe; Naso, Agostino

doi:10.1016/j.lfs.2016.02.019

Cited by 31 publications

(35 citation statements)

References 42 publications

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“…The findings of our study document that patients with end-stage renal disease (ESRD) on dialysis with permanent AF show an increased MYPT-1 phosphorylation and increased Cx40 level when compared to either patients with ESRD on dialysis without AF or healthy controls. These findings reinforce the results of our previous studies in chronic renal failure patients and ESRD patients on dialysis [19]. Patients on dialysis without AF did not have increased Cx40, and thus only the AF subset of dialysis patients have increased levels of MYPT-1 phosphorylation and Cx40, which shows a positive linear correlation.…”

Section: Discussionsupporting

confidence: 90%

“…RhoA/ROCK activation declined after six months of treatment with the AT1R blocker olmesartan [26], suggesting that the RhoA/ROCK pathway plays a major role in the development and maintenance of hypertension [9]. MYPT-1 is the catalytic domain of the myosin light chain phosphatase, and the inhibition of MYPT-1 activity by ROCK is the key mechanism involved in cardiovascular-renal remodeling [19]. MYPT-1 is, in fact, the target of ROCK, which, via an inhibitory phosphorylation of MYPT-1 increases the activity of myosin light chain kinase leading to cardiovascular-renal remodeling [9].…”

Section: Discussionmentioning

confidence: 99%

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

Calò

Ravarotto

Bertoldi

et al. 2020

JCM

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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

Calò

Ravarotto

Bertoldi

et al. 2020

JCM

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“…154 In humans, leukocyte ROCK levels are 4.5 times higher in patients with LVH and hypertension compared to those with hypertension without LVH and ROCK activity also is increased with LVH in chronic kidney disease. 95,96 Statins increase NO bioavailability, which increases myocardial blood flow under hypoxic conditions and inhibits IL-6, IL-8, and vascular cell adhesion molecule-1 (VCAM-1). 155-157 In vitro studies show that statins reduce mitochondrial dysfunction and cardiomyocyte death.…”

Section: Cellular Effects Of Statinsmentioning

confidence: 99%

Pleiotropic Effects of Statins on the Cardiovascular System

Oesterle

Laufs

Liao

2017

Circulation Research

948

684

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The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors (statins), have been used for thirty years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol (LDL-C). Statins may exert cardiovascular protective effects that are independent of LDL-C lowering called “pleiotropic” effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small guanosine triphosphate binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of pro-inflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify since the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-C reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease.

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“…The mechanism of pressure overload induced cardiac remodeling is sophisticated, and much attention has focused on oxidase system of myocardial mitochondria. RhoA/Rho kinase (ROCK) pathway is known to upregulate NADPH oxidases thereby causing overproduction of free radicals and RhoA/ROCK signaling is deeply involved in the cardiovascular effects of oxidative stress . Endogenous reactive oxygen species appear to play important roles in modulating normal cellular processes and the intracellular antioxidant system can balance the effect of reactive oxygen species under normal conditions, under abnormal condition, the antioxidant mechanism is undermined and reactive oxygen species‐induced tissue damage can take place .…”

Section: Discussionmentioning

confidence: 99%

Fasudil alleviates pressure overload‐induced heart failure by activating Nrf2‐mediated antioxidant responses

Guan

Liang

Wang

2018

J of Cellular Biochemistry

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The RhoA/Rho-kinase cascade plays an important role in many aspects of cardiovascular function. This study aims to investigate the protective effects of fasudil, a Rho-kinase inhibitor, on pressure overload induced heart failure in rats. Pressure overload induced heart failure was induced in SD rats by banding the abdominal aorta for 8 weeks. The rats were divided into four groups: Sham, TAC, TAC plus low dose of fasudil, and TAC plus high dose of fasudil group. Low dose and high dose fasudil were 5 and 10 mg/kg/day, respectively. Rats in the Sham and TAC groups were treated with vehicle. Fasudil effectively inhibited TAC-induced heart failure, as evaluated by echocardiography and transmission electron microscopy. Fasudil could significantly promote superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity and significantly decrease malondialdehyde (MDA) content in a dose-dependent maner in TAC rats. Consistently, fasudil evoked significant nuclear translocation of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) with increased DNA/promoter binding and transactivation of Nrf2 targets. In addition, fasudil increased the content of iron as well as transferrin receptor 1 (TfR1) in TAC rats. A mild oxidative stress induced by iron may activate the antioxidant enzymes by feedback response. Taken together, these results indicate that the protective effect of fasudil may be due to its strong antioxidative activities which related with the activated Nrf2 and its down-regulated genes. These findings provide a new treatment concept and support the benefit of fasudil treatment in heart failure.

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Increased rho kinase activity in mononuclear cells of dialysis and stage 3–4 chronic kidney disease patients with left ventricular hypertrophy: Cardiovascular risk implications

Cited by 31 publications

References 42 publications

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

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

Pleiotropic Effects of Statins on the Cardiovascular System

Fasudil alleviates pressure overload‐induced heart failure by activating Nrf2‐mediated antioxidant responses

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