Abstract 505: Specific Activation of the Ang all/AT1R-Jak2-Rho Kinase Pathway in Salt Sensitive but not in Salt Independent Hypertension: Clinical and Pathophysiologically Implications
In hypertension aortic (Ao) stiffness is a main determinant of increased systolic (SBP) and pulse- pressure (PP). Brachial and Ao SBP and PP often differ; Ao pressures predict cardiovascular events more accurately than brachial pressures. It is surmised that increased pressure-workload is cause and effect of Ao stiffening but the mechanisms involved are poorly understood. Rho Kinase is a master regulator of vascular tone and remodeling: In endothelium Rho kinase decreases eNOS expression and NO production. In VSMC Ang II/ AT1R specifically activates Rho Kinase via phosphorylation of Jak2 /Arhgef1 which phosphorylates (inhibits) myosin light chain phosphatase (MYPT1) thereby promoting vasoconstriction. Groups (n= 6) of Dahl SS (DS) rats fed either 0.5% or 4% NaCl diets for 10 weeks were matched with SHR of similar age (6 and 16weeks old) and SBP (147+8 & 211+7). Hypertensive DS rats, but not SHR showed increased Ao weight/length (17%, P<0.05) and left ventricle weight/ body weight ratios (16%, P<0.05). Compared to normotensive DS, Ao AT1Rs in hypertensive DS rose 230% accompanied by increased pJak2/Jak2 (3.5 fold) and pMYPT1/MYPT1 (3.95 fold) all p<0.05. Switch of hypertensive DS to a 0.5 % NaCl diet for 4 additional weeks did not reduce either SBP or the activated Ang l1/Rho Kinase pathways. The ARB Candesartan prevented Angll/AT1-Jak2-Rho Kinase activation in hypertensive DS fed 4% NaCl diet and normalized SBP, LVH and Ao weight/length in hypertensive DS switched to a 0,5% NaCl diet. Hypertensive SHR did not show Ao upregulation of AT1Rs or activation of the Angll/Jak2-Rho Kinase pathway. These studies show for the first time that in low renin salt sensitive hypertension there is specific Ao activation of the Ang II/Jak2-Rho Kinase pathway that is independent of the severity of SBP.
Clinically the variable end-organ disease observed in individuals with similar severity of hypertension may be linked, at least in part, to genetically conditioned differences in Angll/AT1R, Jak-2 activation in response to high dietary salt. These novel studies extend and complement previous studies by us and others implicating abnormal bioactivity of NO and aldosterone in salt sensitive hypertension and unravel a new and intricate pathway in which Rho Kinase plays a pivotal role.
- © 2012 by American Heart Association, Inc.