AIM: To investigate whether KCNE2 participates in the development of pathological hypertrophy. METHODS: Bidirectional manipulations of KCNE2 expression were performed by adenoviral overexpression of KCNE2 or knockdown of KCNE2 with RNA interference in PE-induced neonatal rat ventricular myocytes. Then overexpression of KCNE2 in mouse model of left ventricular hypertrophy induced by transverse aortic constriction( TAC) by ultrasound microbubble-mediated gene transfer were used to detect the therapeutic function of KCNE2 in the development of hypertrophy. RESULTS: KCNE2 expression was significantly decreased in PE-induced hypertrophic cardiomyocytes and in hypertrophic hearts produced by TAC. Knockdown of KCNE2 in cardiomyocytes reproduced hypertrophy,whereas overexpression of KCNE2 attenuated PE-induced cardiomyocyte hypertrophy. Knockdown of KCNE2 increased calcineurin activity and nuclear NFAT protein level,and pretreatment with nifedipine or FK506 attenuated decreased KCNE2-induced cardiomyocyte hypertrophy. Overexpression of KCNE2 in heart by ultrasound microbubble-mediated gene transfer suppressed the development of hypertrophy and activation of calcineurin-NFAT and MAPK pathways in TAC mice. CONCLUSION: These findings demonstrate that cardiac KCNE2 expression is decreased and contributes to the development of hypertrophy via activation of calcineurin-NFAT and MAPK pathways. AIMS: To investigate whether KCNE2 participates in the development of pathological hypertrophy. METHODS: Bidirectional manipulations of KCNE2 expression were performed by adenoviral overexpression of KCNE2 or knockdown of KCNE2 with RNA interference in PE-induced neonatal rat ventricular myocytes. Then overexpression of KCNE2 in mouse model of left ventricular hypertrophy induced by transverse aortic constriction (TAC) by ultrasound microbubble-mediated gene transfer were used to detect the therapeutic function of KCNE2 in the development of hypertrophy. RESULTS: KCNE2 expression was significantly less in PE-induced hypertrophic cardiomyocytes and in hypertrophic hearts produced by TAC. Knockdown of KCNE2 in cardiomyocytes reproduced hypertrophy, overexpression of KCNE2 attenuated PE-induced cardiomyocyte hypertrophy. Knockdown of KCNE2 increased calcineurin activity and nuclear NFAT protein level, and pretreatment with nifedipine or FK506 attenuated decreased KCNE2-induced c Overexpression of KCNE2 in heart by ultrasound microbubble-mediated gene transfer suppressed the development of hypertrophy and activation of calcineurin-NFAT and MAPK pathways in TAC mice. CONCLUSION: These findings demonstrate that cardiac KCNE2 expression is decreased and contributes to the development of hypertrophy via activation of calcineurin-NFAT and MAPK pathways.