Abstract 52: Human Grk4{gamma}142v, Via Histone Deacetylase 1, Produces At1r-dependent Hypertension [Oral Session VII: Concurrent A Clinical Issues]

Human gene variants account for only a small proportion of essential hypertension in humans and have not been shown to produce hypertension in transgenic mice. The association between hypertension and 11 allelic variants of 8 candidate genes in humans (n=1074) was studied. We also evaluated the response to angiotensin receptor blockers (ARBs) in humans (n=681) and transgenic mice generated to express the human wild-type G protein-coupled receptor kinase 4 (hGRK4WT) or the 142V allele (hGRK4142V). hGRK4 variants (R65L, A142V, and A486V) were associated with essential hypertension; hGRK4142V, by itself, predicted the hypertensive phenotype (60% accuracy); hGRK4142V also interacted with GNB3 and PAI-1. Human hypertensive carriers of hGRK4142V (n=68) had a greater decrease in systolic blood pressure (SBP mm Hg, 19.36, vs. 14.58, P=0.001) in response to ARBs than non-carrier (n=135) hypertensives. hGRK4WT transgenic mice (anesthetized, n=42; conscious [n=12, day=118±0.8, night=131±1]) were normotensive while hGRK4142V mice (anesthetized, n=54;conscious [n=12, day=128±2, night=148±3]) had hypertension, increased renal AT1R expression due to decreased histone deacetylase 1 (HDAC1) activity, a greater pressor response to angiotensin II (1000 ng/kg/minX30’)(n=6-9/group, WT=+14±4%, 142V=+26±3%), and a greater fall in SBP with candesartan (2mg/kg/dayX4d) (n=7/group, WT=-5±2%,142V=-29±3%); deletion of Agtr1a normalized the hig...

Source: Hypertension - October 30, 2013 Category: Cardiology Authors: Jose, P., Wang, Z., Sanada, H., Yoneda, M., Zheng, C., Williams, S., Bartlett, J., White, M., Gordon, L., Liu, M., Konkalmatt, P., Wang, X., Asico, L., Villar, V. A., Jones, J., Armando, I., Felder, R., Eisner, G. Tags: Oral Session VII: Concurrent A Clinical Issues Source Type: research