Abstract 9386: ASK2 is a Novel Factor Associated with Salt-Sensitive Hypertension

Abstract

Background: Apoptosis signal-regulating kinase(ASK)1 and ASK2 are MAP3Ks activated by oxidative stress. We have shown that ASK1 has a pivotal role in cardiovascular diseases. ASK2 has been identified as a binding protein for ASK1, and both ASK1 and ASK2 control their respective activities. Cardiovascular phenotypes of ASK2 deficient mice (ASK2KO) have not been reported. Methods and Results: We confirmed ASK2 mRNA expression in hearts, aortas, and kidneys utilizing in situ hybridization . ASK2KO had different phenotypes from ASK1 deficient mice (ASK1KO); ASK2KO have hypertension with significant cardiac hypertrophy and fibrosis. To further characterize the hypertension of ASK2KO, we implanted telemetry units in mice to monitor 24 h variability of blood pressure (BP) and heart rates. ASK2KO had a circadian rhythm in BP, and the differences in systolic BP between ASK2KO and WT was greater in dark periods than in light periods. There were no differences in locomotor activities or heart rates between ASK2KO and WT. There were no significant differences between ASK2KO and WT in sympathetic nerve activities or in parameters pertaining to the renin-angiotensin system. The ratio of ASK2KO urine Na/K in dark was lower than that in WT, and urine Ca excretion in ASK2KO was greater than in WT, suggesting that ASK2KO have renal tubular dysfunctions. We fed a high-salt diet to ASK2KO to examine salt sensitivity. Telemetry analysis revealed that blood pressure of ASK2KO was increased by high-salt diets; furthermore, high salt diets-induced BP differences between ASK2KO and WT were greater in dark than in light. High salt-induced urine Ca excretion levels were significantly greater in ASK2KO than in WT. Heart weights of ASK2KO were higher than those of WT at 8 days after a high-salt diet. ASK2KO therefore have salt sensitive hypertension with cardiac hypertrophy, and there are significant differences in renal excretion levels of electrolytes between ASK2KO and WT. Hypertension of ASK2KO does not depend upon the presence of ASK1 because ASK2 and ASK1 double deficient mice also have hypertension. Conclusion: ASK2 is a novel factor that is involved in the pathogenesis of salt-sensitive hypertension.