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

Life Sci. 2016 Mar 1:148:80-5. doi: 10.1016/j.lfs.2016.02.019. Epub 2016 Feb 9.

Abstract

Aims: 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.

Materials and 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.

Key findings: 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).

Significance: 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.

Keywords: CKD; Dialysis; Fasudil; LVH; MYPT-1; Rho kinase.

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Adult
  • Aged
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Female
  • Humans
  • Hypertrophy, Left Ventricular / diagnosis
  • Hypertrophy, Left Ventricular / enzymology*
  • Hypertrophy, Left Ventricular / epidemiology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / enzymology*
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors / pharmacology
  • Renal Dialysis / adverse effects
  • Renal Dialysis / trends*
  • Renal Insufficiency, Chronic / diagnosis
  • Renal Insufficiency, Chronic / enzymology*
  • Renal Insufficiency, Chronic / epidemiology
  • Risk Factors
  • rho-Associated Kinases / metabolism*

Substances

  • Protein Kinase Inhibitors
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • rho-Associated Kinases
  • fasudil