The blocking of angiotensin II type 1 receptor and RhoA/Rho kinase activity in hypertensive patients: Effect of olmesartan medoxomil and implication with cardiovascular-renal remodeling

J Renin Angiotensin Aldosterone Syst. 2015 Dec;16(4):1245-50. doi: 10.1177/1470320315594324. Epub 2015 Aug 3.

Abstract

Hypothesis/introduction: The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase activation and production of proinflammatory cytokines/growth factors leading to cardiovascular-renal remodeling. Ang II stimulates the RhoA/Rho kinase (ROCK) pathway, which is deeply involved in the development of cardiovascular-renal remodeling via OxSt induction. Olmesartan, an Ang II type 1 receptor blocker, possesses antioxidant and activating nitric oxide system-related effects, which we have shown in terms of p22(phox) reduction, heme oxygenase-1 and calcitonin gene-related peptide increase. This study evaluates in 15 untreated hypertensive patients the effect of olmesartan treatment on p63RhoGEF, key in Ang II-induced ROCK activation, and MYPT-1 phosphorylation, a marker of ROCK activity.

Materials and methods: The p63RhoGEF protein level and MYPT-1 phosphorylation (Western blot) were evaluated at baseline, and after three and six months of olmesartan treatment.

Results: Olmesartan normalized systolic and diastolic BP (p < 0.001), reduced p63RhoGEF level: 1.3±0.25 d.u. (baseline) vs 1.0±0.29 (three months), p < 0.0001 vs 1.0±0.22, (six months), p < 0.0001 and MYPT-1 phosphorylation: 1.2 ±0.14 (baseline) vs 0.9±0.19 (three months), p = 0.008, vs 0.8±0.16 (six months), p = 0.001.

Conclusions: These data added to our previous results further provide a mechanistic rationale for olmesartan's antioxidant/anti-inflammatory potential translation, in the long term, toward anti-atherosclerotic/anti-remodeling effects reported by clinical trials.

Keywords: Rho kinase; angiotensin II signaling; cardiovascular-renal remodeling; hypertension; olmesartan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use*
  • Blood Pressure / drug effects
  • Cardiovascular System / drug effects
  • Cardiovascular System / physiopathology*
  • Densitometry
  • Diastole / drug effects
  • Female
  • Humans
  • Hypertension / drug therapy*
  • Hypertension / physiopathology
  • Kidney / drug effects
  • Kidney / physiopathology*
  • Male
  • Middle Aged
  • Myosin-Light-Chain Phosphatase / metabolism
  • Olmesartan Medoxomil / pharmacology
  • Olmesartan Medoxomil / therapeutic use*
  • Phosphorylation / drug effects
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • Systole / drug effects
  • rho-Associated Kinases / antagonists & inhibitors*
  • rho-Associated Kinases / metabolism
  • rhoA GTP-Binding Protein / antagonists & inhibitors*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • ARHGEF25 protein, human
  • Angiotensin II Type 1 Receptor Blockers
  • Receptor, Angiotensin, Type 1
  • Rho Guanine Nucleotide Exchange Factors
  • Olmesartan Medoxomil
  • rho-Associated Kinases
  • Myosin-Light-Chain Phosphatase
  • PPP1R12A protein, human
  • rhoA GTP-Binding Protein