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Increased level of p63RhoGEF and RhoA/Rho kinase activity in hypertensive patients

Calò, Lorenzo A.a; Davis, Paul A.b; Pagnin, Elisaa; Dal Maso, Luciaa; Maiolino, Giuseppea; Seccia, Teresa M.a; Pessina, Achille C.a; Rossi, Gian Paoloa

doi: 10.1097/HJH.0000000000000075
ORIGINAL PAPERS: Pathophysiological aspects

Objective: p63RhoGEF, a guanine nucleotide exchange factor, has been reported ‘in vitro’ as key mediator of the angiotensin II-induced RhoA/Rho kinase activation leading to vasoconstriction and cardiovascular remodeling. We assessed p63RhoGEF gene and protein expression and RhoA/Rho kinase activity in essential hypertensive and Bartter's and Gitelman's syndrome patients, a human model opposite to hypertension; the latter have, in fact, increased plasma angiotensin II, activation of the renin–angiotensin system, yet normotension/hypotension, reduced peripheral resistance and lack of cardiovascular remodeling due to an endogenously blunted angiotensin II type 1 receptor signaling.

Methods: Mononuclear cell p63RhoGEF gene and protein expression and the phosphorylation status of the myosin phosphatase target protein-1 (MYPT-1), marker of Rho kinase activity, were assessed in essential hypertensive patients, Bartter's/Gitelman's patients and healthy individuals by quantitative real-time PCR and western blot.

Results: p63RhoGEF mRNA and protein level and MYPT-1 phosphorylation status were higher in hypertensive patients and lower in Bartter's/Gitelman's patients compared with healthy individuals: p63RhoGEF mRNA level: 0.59 ± 0.17 ΔΔCt vs. 0.37 ± 0.17 vs. 0.20 ± 0.19, analysis of variance (ANOVA): P <0.016; p63RhoGEF protein level 1.35 ± 0.14 vs. 1.09 ± 0.05 vs. 0.90 ± 0.09 densitometric units, ANOVA: P <0.0001; MYPT-1: 1.39 ± 0.34 vs. 1.01 ± 0.12 vs. 0.81 ± 0.06, ANOVA: P < 0.0001. p63RhoGEF mRNA was significantly correlated with both SBP and DBP in both hypertensive patients (R = 0.79, P < 0.02 and R = 0.78, P < 0.02) and in Bartter's syndrome/Gitelman's syndrome patients (R = 0.87, P < 0.001 and R = 0.86, P < 0.001), respectively.

Conclusion: Increased p63RhoGEF mRNA and protein level and Rho kinase activity are shown for the first time in essential hypertensive patients, whereas the opposite was found in Bartter's/Gitelman's patients, a human model opposite to hypertension. These results combined with other ‘in-vitro’ studies strongly support the crucial importance of p63RhoGEF in Ang II-mediated signaling involved in the regulation of blood pressure and its long-term complications in humans.

aDepartment of Medicine, University of Padova, Padova, Italy

bDepartment of Nutrition, University of California, Davis, California, USA

Correspondence to Lorenzo A. Calò, MD, PhD, Department of Medicine (DIMED), ClinicaMedica 4, University of Padova, Via Giustiniani 2, 35128 Padova, Italy. Tel: +39 049 8218701; fax: +39 049 8754179; e-mail:

Abbreviations: AT1R, angiotensin II type 1 receptor; MYPT-1, myosin phosphatase target protein-1; p63RhoGEF, p63 Rho guanine nucleotide exchange factor; PLCβ1, phospholipase C β1

Received 2 July, 2013

Accepted 13 November, 2013

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