title: Increased rho kinase activity in mononuclear cells of dialysis and stage 3-4 chronic kidney disease patients with left ventricular hypertrophy: Cardiovascular risk implications.
abstract: OBJECTIVE
  Cardiovascular disease (CVD) is the leading cause of excess mortality in chronic kidney disease (CKD) and dialysis patients (DP) who have higher prevalence of left ventricular hypertrophy (LVH), the strongest predictor of CV events. Rho kinase (ROCK) activation is linked in hypertensive patients to cardiac remodeling while ROCK inhibition suppresses cardiomyocyte hypertrophy and, in a human clinical condition opposite to hypertension, its downregulation associates with lack of CV remodeling. Information on ROCK activation-LVH link in CKD and DP is lacking.
  
  
  METHODS
  Mononuclear cells (PBMCs) MYPT-1 phosphorylation, a marker of ROCK activity, and the effect of fasudil, a ROCK inhibitor, on MYPT-1 phosphorylation were assessed in 23 DPs, 13 stage 3-4 CKD and 36 healthy subjects (HS) by Western blot. LV mass was assessed by M-mode echocardiography.
  
  
  RESULTS
  DP and CKD had higher MYPT-1 phosphorylation compared to HS (p<0.001 and p=0.003). Fasudil (500 and 1000μM) dose dependently reduced MYPT-1 phosphorylation in DP (p<0.01). DP had higher LV mass than CKD (p<0.001). MYPT-1 phosphorylation was higher in patients with LVH (p=0.009) and correlated with LV mass both in DP and CKD with LVH (p<0.001 and p=0.006).
  
  
  CONCLUSIONS
  In DP and CKD, ROCK activity tracks with LVH. This ROCK activation-LVH link provided in these CVD high-risk patients along with similar findings in hypertensive patients and added to opposite findings in a human model opposite to hypertension and in type 2 diabetic patients, identify ROCK activation as a potential LVH marker and provide further rationale for ROCK activation inhibition as target of therapy in CVD high-risk patients.
authors.affiliation: Department of Medicine (DIMED), Nephrology, University of Padova, Italy. Electronic address: renzcalo@unipd.it.
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Calò
authors.affiliation: Department of Medicine (DIMED), Nephrology, University of Padova, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Vertolli
authors.affiliation: Department of Medicine (DIMED), Nephrology, University of Padova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pagnin
authors.affiliation: Department of Medicine (DIMED), Nephrology, University of Padova, Italy.
authors.forename: Verdiana
authors.initials: V
authors.lastname: Ravarotto
authors.affiliation: Department of Nutrition, University of California, Davis, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Davis
authors.affiliation: Department of Cardiologic, Thoracic and Vascular Sciences, University of Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Lupia
authors.affiliation: Department of Medicine (DIMED), Nephrology, University of Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Naso
authors.affiliation: Department of Medicine (DIMED), Hypertension, University of Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Maiolino
authors.affiliation: Department of Medicine (DIMED), Nephrology, University of Padova, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Naso
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000368:Aged; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000175:diagnosis / Q000201:enzymology* / Q000453:epidemiology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D006435:Renal Dialysis / Q000009:adverse effects / Q000639:trends*; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000201:enzymology* / Q000453:epidemiology; D012307:Risk Factors; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil
keywords: CKD; Dialysis; Fasudil; LVH; MYPT-1; Rho kinase