title: 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.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Medicine Nephrology, University of Padova-Azienda Ospedaliera Padova, Italy Hypertension Clinic, University of Padova-Azienda Ospedaliera Padova, Italy.
authors.forename: Verdiana
authors.initials: V
authors.lastname: Ravarotto
authors.affiliation: Department of Medicine Nephrology, University of Padova-Azienda Ospedaliera Padova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pagnin
authors.affiliation: Hypertension Clinic, University of Padova-Azienda Ospedaliera Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Maiolino
authors.affiliation: Department of Medicine Nephrology, University of Padova-Azienda Ospedaliera Padova, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fragasso
authors.affiliation: Department of Medicine Nephrology, University of Padova-Azienda Ospedaliera Padova, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Carraro
authors.affiliation: Department of Medicine Nephrology, University of Padova-Azienda Ospedaliera Padova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rossi
authors.affiliation: Department of Medicine Nephrology, University of Padova-Azienda Ospedaliera Padova, Italy renzcalo@unipd.it.
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Calò
mesh_terms: D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology*; D003720:Densitometry; D003971:Diastole / Q000187:drug effects; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D000068557:Olmesartan Medoxomil / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D013599:Systole / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C475063:ARHGEF25 protein, human; D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D064067:Rho Guanine Nucleotide Exchange Factors; D000068557:Olmesartan Medoxomil; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; D020742:rhoA GTP-Binding Protein
keywords: Rho kinase; angiotensin II signaling; cardiovascular-renal remodeling; hypertension; olmesartan