PS 10-04 HYPOTENSIVE EFFECT OF LOSARTAN THROUGH SUPPRESSING LEUKEMIA-ASSOCIATED RhoGEF EXPRESSION IN VASCULAR SMOOTH MUSCLE OF SPONTANEOUSLY HYPERTENSIVE RATS

Abstract

Objective: To elucidate the mechanism that chronic blood pressure (BP) reduction caused by losartan is through the suppression of leukemia-associated Rho guanine nucleotide exchange factors (LARG) expression in vascular smooth muscle cells (VSMCs) of spontaneously hypertensive rats (SHRs). Design and Method: Four-week-old Wistar-Kyoto (WKY) rats and SHRs were treated with Losartan (20 mg/kg/day) for 8 weeks. BP was measured by the tail-cuff method. At 12 weeks, isometric contraction of rat aortic rings was measured with a force transducer and recorder. The target Rho guanine nucleotide exchange factors (RhoGEFs) messenger RNA (mRNA) and protein levels, and the myosin phosphatase target subunit 1 (MYPT-1) phosphorylation extent in aorta were determined using quantitative real-time polymerase chain reaction (qPCR) assay and Western blot analysis, respectively. Results: BP of four-week-old SHRs did not differ from that of age-matched WKY rats, whereas BP increased in twelve-week-old SHRs. Losartan treatment reduced BP in both rats’ strains, with greater extent in SHRs. The contractile force of aortic rings from SHRs treated with losartan was significantly lower than that from non-treated SHRs in response to angiotensin II. LARG protein expression was significantly higher in non-treated SHRs compared to WKY rats. After losartan treatment, both LARG protein level and phosphorylation extent of MYPT-1 were more suppressed in SHRs than in WKY rats. Conclusions: The study shows that chronic reduction of BP by losartan in SHRs is through suppressing LARG expression and MYPT-1 phosphorylation of VSMCs. Administration of losartan at early age of SHRs may help prevent hypertension development.