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Here we revealed that Nmnat2 protein expression and enzyme activity were down\u2010regulated during cardiac hypertrophy. In neonatal rat cardiomyocytes, overexpression of Nmnat2 but not its catalytically inactive mutant blocked angiotensin II (Ang II)\u2010induced cardiac hypertrophy, which was dependent on activation of SIRT6 through maintaining the intracellular NAD level. 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