Abstract 197: Cardiac-specific Activation of Apoptosis Signal-regulating Kinase 1 Leads to Cardiac Dysfunction with Pathological Hypertrophy
Apoptosis signal-regulating kinase 1 (ASK1) is a reactive oxygen species-sensitive MAP kinase kinase kinase, which activates JNK and p38 MAP kinase. We previously reported that ASK1 is involved in not only apoptotic but also non-apototic cardiomyocyte death. We also demonstrated that overexpression of constitutively active mutant of ASK1 (ASKΔN) induced cardiomyocyte hypertrophy in culture, while overexpression of dominant negative ASK1 attenuated hypertrophy. However, ASK1 was reported to negatively regulate calcineurin-NFAT signaling and to reduce hypertrophic grows of cardiomyocyte. Thus, the role of ASK1 in cardiac hypertrophic response is still uncertain. Here, we generated transgenic mice (Tg) expressing ASKΔN with the aid of Cre-lox-P system. The mice were crossbred with mice expressing tamoxifen-inducible Cre recombinase under the control of αMHC promoter to express in cardiac and time specific manner. The expression of ASKΔN protein was observed at day 1 after tamoxifen administration with the peak of day 7 after treatment. Forty percent of Tg were died of heart failure, and the rest showed cardiac dysfunction with decreased LV contraction and increased lung weight-tibia length ratio on day 14. The heart weight-tibia length and LV weight-tibia length were increased in Tg on day 7 with preserved LV contraction. Histological examination demonstrated that cross-sectional area of left ventricular myocyte and ventricular fibrosis were increased in Tg. Phosphorylation of JNK was observed day 2 after administration and sustained there after, but phosphrylation of p38 was observed only in early stage. The number of TUNEL-positive cells was significantly increased in Tg hearts. We analyzed gene expression of Tg using DNA microarray. The correlation of each sample on same day were good (day0 R2 =0.996, day2 R2 =0.997, day 4 R2 =0.987, day 5 R2= 0.997, day 7 R2 =0.993, day 14 R2 =0.996). In this model, marker gene of cardiac pathological hypertrophy such as ANP (day 4–14), BNP (day 2–14) and myosin heavy chain (day 4 –14) were elevated. In conclusion, cardiac specific overexpression of ASKΔN in vivo leads to cardiac dysfunction with cardiac pathological hypertrophy. ASKΔN Tg mice might be a useful model for analyzing heart failure.