The present study demonstrated that SIRT3 were reduced in Ang II induced cardiac hypertrophy. Overexpression of SIRT3 attenuated cardiomyocyte hypertrophy induced by Ang II. On the contrary, knockdown of endogenous SIRT3 or genetic SIRT3 depletion aggravated the hypertrophic response induced by Ang II.

NMNAT3 was a substrate of SIRT3. SIRT3 coulddeacetylate NMNAT3 and enhance its enzyme activity. Knockdown of NMNAT3 attenuated the protective effect of SIRT3 on cardiac hypertrophy, on the contrary, overexpression of NMNAT3 had the opposite effect.

In NRCMs, NAMPT was present in the cytosol, but absent in mitochondria. Moreover, NAMPT was not involved in the anti-hypertrophic effect of SIRT3 in Ang II-induced cardiac hypertrophy.

There could be an intriguing negative feedback regulation loop in Ang II-induced cardiomyocyte hypertrophy. Decreased SIRT3 activity increased acetylation level of NMNAT3, and the subsequent reduced NMNAT3 activity could down-regulate mitochondrial NAD levels. Eventually, the SIRT3 activity was attenuated.