title: NMNAT3 is involved in the protective effect of SIRT3 in Ang II-induced cardiac hypertrophy.
abstract: 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.
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, People's Republic of China.
authors.forename: Zhongbao
authors.initials: Z
authors.lastname: Yue
authors.affiliation: Department of Pharmacy, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, People's Republic of China.
authors.forename: Yunzi
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, People's Republic of China.
authors.forename: Jia
authors.initials: J
authors.lastname: You
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, People's Republic of China.
authors.forename: Zhuoming
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, People's Republic of China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.affiliation: School of Nursing, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong Province, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Lu
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, People's Republic of China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, People's Republic of China. Electronic address: chshaor@mail.sysu.edu.cn.
authors.forename: Shaorui
authors.initials: S
authors.lastname: Chen
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, People's Republic of China; National and Local Joint Engineering Laboratory of Druggability Assessment and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, People's Republic of China. Electronic address: liupq@mail.sysu.edu.cn.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
mesh_terms: D000107:Acetylation; D000804:Angiotensin II; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002316:Cardiotonic Agents / Q000378:metabolism*; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D012333:RNA, Messenger; D000804:Angiotensin II; D054409:Nicotinamide Phosphoribosyltransferase; C529445:NMNAT3 protein, rat; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C000592579:nicotinamide mononucleotide adenylyltransferase 3, mouse; D056566:Sirtuin 3
keywords: Cardiac hypertrophy; NMNAT3; SIRT3