Abstract 1759: ASK2 Deficient Mice Have Elevated Blood Pressures with Cardiac Hypertrophy and Remodeling
Apoptosis signal-regulating kinase (ASK) 1 is a MAPKKK that is activated in response to various stresses, including oxidative stress. ASK2, which is a highly related kinase to ASK1, forms a stable heteromeric complex with ASK1 in mammalian cells. There have been no reports about the functions of ASK2 in vivo. Herein, we show for the first time, the cardiovascular phenotypes of ASK2 deficient mice (ASK2KO). (1) ASK2KO have higher blood pressures than wild type mice (WT) (122 ± 1 vs. 104 ± 0.4 mmHg, p < 0.01). Neither daily water intake nor urine volume were significantly different in the two groups. Urinary catecholamine excretion in ASK2KO was significantly increased compared to WT, indicating that high blood pressures in ASK2KO are associated with enhanced sympathetic nerve activity. 24-hour urinary nitrate/nitrite (NOx) excretion levels in ASK2KO were higher than WT, suggesting that NO increasing in ASK2KO may be a compensatory change. No differences were observed in vascular relaxation due to acetylcholine between ASK2KO and WT. Left ventricular weight of ASK2KO was larger than WT (3.1 ± 0.1 vs. 2.9 ± 0.1 mg/g, p < 0.05). Histological examination revealed that perivascular and interstitial myocardial fibrosis were increased in ASK2KO compared to WT. The number of macrophages in heart tissue was greater in ASK2KO than in WT. These phenotypes were quite different from ASK1 deficient mice that have normal blood pressures and a tolerance to various cardiovascular stresses. (2) We examined whether hypertension and myocardial fibrosis in ASK2KO is associated with the renin-angiotensin system (RAS). ASK2KO were orally given olmesartan (3.5mg/kg/day) or hydralazine (4mg/kg/day). Although blood pressures of both groups were decreased to the same levels as WT, only the olmesartan group had decreased left ventricular weight and decreased levels of urinary catecholamine excretion. This data indicates that hypertension and cardiac hypertrophy in ASK2KO are associated with RAS activation and sympathetic nerve activation. Unlike ASK1KO, ASK2KO have elevated blood pressures with cardiac hypertrophy and remodeling, and ASK2 plays an important role in hypertension and cardiac hypertrophy.