Abstract 5538: Apoptosis Signal-Regulating Kinase (ASK) 2 Deficient Mice Have Salt-Resistant Hypertension With Cardiac Hypertrophy
Background: Apoptosis signal-regulating kinase (ASK) 2 is a MAP3K that is highly related to ASK1. ASK2 is activated in response to oxidative stress. There have been no reports about the cardiovascular functions of ASK2. Herein, we show the cardiovascular phenotypes of ASK2 deficient mice (ASK2KO).
Methods and Results:
ASK2KO had higher blood pressures than wild type mice (WT) (122±1 vs. 104±0.4 mmHg, p<0.01). Urinary catecholamine excretion in ASK2KO was significantly increased compared to WT, indicating that hypertension in ASK2KO is associated with enhanced sympathetic nerve activity. Histological examinations revealed that myocardial fibrosis was increased in ASK2KO compared to WT. The number of macrophages and superoxide levels were greater in ASK2KO than in WT.
ASK2KO were administered either olmesartan or hydralazine in order to determine if myocardial fibrosis in ASK2KO is associated with the renin-angiotensin system (RAS). Although blood pressures of both groups were decreased to the same levels as normal WT levels, only the olmesartan group had both decreased myocardial fibrosis and inflammatory cell infiltration; this indicates that cardiac hypertrophy in ASK2KO is associated with RAS.
ASK2KO and WT were fed a high salt diet (8% NaCl) to examine whether hypertension in ASK2KO is salt-sensitive or not.
Blood pressures of ASK2KO were significantly decreased by salt loading, although those of WT were not. Increased cardiac fibrosis and inflammatory cell infiltration observed in normal diet ASK2KO were also significantly decreased by salt loading. This shows that hypertension and cardiac hypertrophy in ASK2KO are salt resistant. Salt loading increased ASK2 mRNA in the heart tissues of WT, and it enhanced the inflammatory responses, oxidative stress and TGFβ expression in WT hearts, but these effects were not observed in ASK2KO, which indicates that ASK2 is involved in salt induced cardiac injury.
ASK2KO have salt-resistant hypertension with cardiac hypertrophy. ASK2 plays an important role in blood pressure regulation and cardiac hypertrophy in association with RAS.
ASK2 plays a pivotal role in salt-induced cardiac injuries in association with oxidative stress and inflammatory responses.