Research ArticleNMNAT3 is involved in the protective effect of SIRT3 in Ang II-induced cardiac hypertrophy

- 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.

Pathological cardiac hypertrophy is a maladaptive response in a variety of organic heart disease (OHD), which is characterized by mitochondrial dysfunction that results from disturbed energy metabolism. SIRT3, a mitochondria-localized sirtuin, regulates global mitochondrial lysine acetylation and preserves mitochondrial function. However, the mechanisms by which SIRT3 regulates cardiac hypertrophy remains to be further elucidated. In this study, we firstly demonstrated that expression of SIRT3 was decreased in Angiotension II (Ang II)-treated cardiomyocytes and in hearts of Ang II-induced cardiac hypertrophic mice. In addition, SIRT3 overexpression protected myocytes from hypertrophy, whereas SIRT3 silencing exacerbated Ang II-induced cardiomyocyte hypertrophy. In particular, SIRT3-KO mice exhibited significant cardiac hypertrophy. Mechanistically, we identified NMNAT3 (nicotinamide mononucleotide adenylyltransferase 3), the rate-limiting enzyme for mitochondrial NAD biosynthesis, as a new target and binding partner of SIRT3. Specifically, SIRT3 physically interacts with and deacetylates NMNAT3, thereby enhancing the enzyme activity of NMNAT3 and contributing to SIRT3-mediated anti-hypertrophic effects. Moreover, NMNAT3 regulates the activity of SIRT3 via synthesis of mitochondria NAD. Taken together, these findings provide mechanistic insights into the negative regulatory role of SIRT3 in cardiac hypertrophy.

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