Abstract 13837: ASK2 Deficiency Causes Hypertension and Cardiac Fibrosis Independently of the Presence of ASK1 ∼ Investigation with ASK1/2 Double Deficient Mice
Background:ASK1 and ASK2 are MAP3Ks that are activated by oxidative stress. We have reported that ASK1 deficient mice (ASK1KO) are tolerant to various cardiovascular diseases. There have been no reports about the cardiovascular phenotypes of ASK2 deficient mice (ASK2KO), even though ASK2 has been identified as a binding protein for ASK1. Herein, we examined both physiological and pathological functions of ASK2; moreover, we examined the interactions between ASK1 and ASK2.
Methods and Results: 1) We compared cardiovascular phenotypes in wild type mice (WT), ASK1KO, ASK2KO, and ASK1/ASK2 double deficient mice (ASK1/2DKO). 12 week-old ASK2KO and ASK1/2DKO had higher blood pressures than WT and ASK1KO. Cardiac fibrosis in 17 week-old ASK2KO and ASK1/2DKO was significantly increased compared to WT and ASK1KO. Thus, ASK2 deficiency induced hypertension and cardiac fibrosis, and these two phenotypes were not affected by the presence or absence of ASK1. 2) We examined the effects of Angiotensin II (AngII) induced cardiovascular injuries in these mice. Four-weeks of AngII infusion (600ng/kg/min) increased blood pressures to the same relative degree in all groups. Though heart weights of WT and ASK2KO were significantly increased by the AngII infusion, those of ASK1KO and ASK1/2DKO were less affected by it. Histological examinations revealed that cardiac fibrosis was increased in WT and ASK2KO by AngII, but it was not increased in ASK1KO and ASK1/2DKO. The number of CD68 positive cells in heart tissues showed a similar tendency to the levels of cardiac fibrosis. This data showed that the AngII-induced cardiac fibrosis and inflammation were ASK1-dependent. Finally, we examined acetylcholine-mediated vascular relaxation. AngII-induced endothelial dysfunction in WT was not observed in ASK1KO, ASK2KO, or ASK1/2DKO.
Conclusions: 1) ASK2KO have two different cardiovascular phenotypes from ASK1KO: hypertension; and, cardiac hypertrophy. 2) Hypertension and cardiac hypertrophy in ASK2KO do not depend on the presence of ASK1. 3) AngII-induced cardiac hypertrophy and inflammation are ASK1-dependent effects. 4) AngII-induced endothelial dysfunction is associated with both ASK1 and ASK2.
- © 2010 by American Heart Association, Inc.