Verdiana Ravarotto1, Elisa Pagnin2, Giuseppe Maiolino3, Antonio Fragasso2, Gianni Carraro2, Barbara Rossi2, Lorenzo A Calò4. 1. Department of Medicine Nephrology, University of Padova-Azienda Ospedaliera Padova, Italy Hypertension Clinic, University of Padova-Azienda Ospedaliera Padova, Italy. 2. Department of Medicine Nephrology, University of Padova-Azienda Ospedaliera Padova, Italy. 3. Hypertension Clinic, University of Padova-Azienda Ospedaliera Padova, Italy. 4. Department of Medicine Nephrology, University of Padova-Azienda Ospedaliera Padova, Italy renzcalo@unipd.it.
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.
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.
Authors: Jakobus van Unen; Taofei Yin; Yi I Wu; Marieke Mastop; Theodorus W J Gadella; Joachim Goedhart Journal: Sci Rep Date: 2016-11-11 Impact factor: 4.379
Authors: S A Potthoff; S Stamer; K Grave; E Königshausen; S H Sivritas; M Thieme; Y Mori; M Woznowski; L C Rump; J Stegbauer Journal: J Renin Angiotensin Aldosterone Syst Date: 2016-07-12 Impact factor: 1.636
Authors: Lorenzo A Calò; Verdiana Ravarotto; Giovanni Bertoldi; Elisa Pagnin; Barbara Rossi; Matteo Rigato; Paul A Davis; Riccardo Proietti Journal: J Clin Med Date: 2020-01-07 Impact factor: 4.241