Abstract 1173: Gq Signaling Mediates High Blood Pressure and Hypertrophy in Two Divergent Models of Hypertension
Hypertension (HBP) is associated with increased levels of AngII and NE, which bind to Gq-coupled receptors. Many animal models and humans with HBP have increased levels of G protein receptor kinase 2 (GRK2) in vascular smooth muscle(VSM), which causes HBP. We tested whether inhibiting VSM Gq signaling by expressing of an intracellular peptide (GqI) decreased HBP and cardiac hypertrophy, in two divergent murine models of HBP: the 2 kidney, 1 clip (2K1C)model and a genetic mouse model that overexpresses G protein receptor kinase 2 (GRK2) in VSM.
Methods: GqI mice and their non-transgenic littermate controls (C) were subjected to 2K1C. Conscious BP was measured via radiotelemetry and echo(m-mode) was performed before and 4 wks post 2K1C. Increasing doses of AngII were added to aortic rings. To test the efficacy of GqI in the 2K1C model, we also treated mice with Losartan, an AngII-receptor blocker. We crossbred GRK2 mice (have HBP) with GqI. We measured BP, echo, and did immunohistology on these hearts.
Results: GqI mice had lower BP vs. C after 2K1C (111 ± 3 vs. 125 ± 4 mmHg, n = 8,8). Although, there was a decrease in BP in GqI mice following 2K1C, cardiac hypertrophy still occurred. There were similar increases in ventricular wall thickness (VWT) between C and GqI 4 weeks post 2K1C (C: 1.00 ±.05 vs. .79 ±.03 mm, n = 10,15; GqI: .93 ± .03 vs. .76 ± .02 mm, n = 20,19). There were also similar decreases in cardiac function after 2K1C measured by fractional shortening (FS) in C (35.7 ± 1.3 vs. 26.0 ± 1.9%, n = 10,15) and GqI (34.2 ± 0.8 vs. 25.9 ± 1.4, n = 20,19). The dose response curve to AngII in aortic rings was right-shifted 2.4 fold in GqI mice vs. C, suggesting decreased AngII sensitivity in GqI mice. Losartan normalized VWT in both C and GqI after 2K1C (0.77 ± .03 and 0.77 ± .02 mm) and FS (32.9 ± 0.7 and 32.0 ± 0.9%, n = 10,8). Hybrid GRK2/GqI mice had decreased BP vs. GRK2 (87.5 ± 6.3 vs. 111.6 ± 3.1 mmHg, n = 5,7). Hybrid GRK2/GqI mice also had less VSM hypertrophy than GRK2 (23.8 ± 1.9 vs. 32.9 ± 2.5 um, n = 6,3).
Conclusions: We show that Gq signaling is important in 2 models of HBP. It appears that Gq signaling contributes to high BP through both AngII signaling and VSM hypertrophy. These data suggests that inhibition of VSM Gq signaling may provide future therapeutic strategies to treat HBP and HF.