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Nmnat2 Protects Cardiomyocytes from Hypertrophy Via Activation of SIRT6

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Nmnat2 Protects Cardiomyocytes from Hypertrophy Via Activation of SIRT6 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 586 (2012) 866–874 journal homepage: www.FEBSLetters.org Nmnat2 protects cardiomyocytes from hypertrophy via activation of SIRT6 ⇑ Yi Cai a,1, Shan-Shan Yu b,1, Shao-Rui Chen a, Rong-Biao Pi a, Si Gao a, Hong Li a, Jian-Tao Ye a, , ⇑ Pei-Qing Liu a, a Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China b Department of Pharmaceutical Science, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China article info abstract Article history: The discovery of sirtuins (SIRT), a family of nicotinamide adenine dinucleotide (NAD)-dependent Received 25 October 2011 deacetylases, has indicated that intracellular NAD level is crucial for the hypertrophic response of Revised 4 January 2012 cardiomyocytes. Nicotinamide mononucleotide adenylyltransferase (Nmnat) is a central enzyme Accepted 12 February 2012 in NAD biosynthesis. Here we revealed that Nmnat2 protein expression and enzyme activity were Available online 20 February 2012 down-regulated during cardiac hypertrophy. In neonatal rat cardiomyocytes, overexpression of Edited by Zhijie Chang Nmnat2 but not its catalytically inactive mutant blocked angiotensin II (Ang II)-induced cardiac hypertrophy, which was dependent on activation of SIRT6 through maintaining the intracellular NAD level. Our results suggested that modulation of Nmnat2 activity may be beneficial in cardiac Keywords: Nmnat2 hypertrophy. Cardiac hypertrophy Ó 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Sirtuin 6 NAD Ang II 1. Introduction ure. However, the molecular mechanisms underlying sirtuin-medi- ated cardioprotection and how the functions of sirtuins are A variety of stress-responsive signaling pathways promote car- regulated under the circumstance of cardiomyopathy remain to be diac hypertrophy, but the mechanisms that link these pathways clarified. are only beginning to be unveiled. The sirtuin (SIRT) family, which Nicotinamide adenine dinucleotide (NAD) is a classic coenzyme belongs to class III of histone deacetylases (HDACs), is implicated with a well-established role in cellular redox reactions. Recently, in the control of critical cellular processes such as differentiation, several lines of evidence have implicated NAD biochemistry in a proliferation, apoptosis, metabolism and aging [1,2]. In mammals, broad range of biological functions [6,7]. It’s now known that the there are seven sirtuin family members named SIRT1-7. Recently, activity of sirtuins, as NAD-dependent histone deacetylases, is sus- SIRT1, SIRT3, and SIRT7 have been proved to play important roles ceptible to the availability of NAD content, and reduced cellular in physiological and pathological cardiac growth [3–5]. Our previ- levels of NAD attenuate the SIRT deacetylase activity [8]. A recent ous study have also demonstrated that SIRT6 is inactivated during study reported that NAD could repress the agonist-induced cardiac Ang II-induced cardiac hypertrophy, and increased activity of SIRT6 hypertrophy by mediating the activation of SIRT3 but not SIRT1 [9]. protects cardiomyocytes from hypertrophic response by suppress- Consistently, we found that the deacetylase activity of SIRT6 drops ing NFjB activation (Supplementary Fig. S1). These findings conver- along with the intracellular NAD level during cardiac hypertrophy, gently suggest that sirtuins may be potential targets for the indicating a close relationship between NAD and SIRT6 in heart prevention and/or treatment of cardiac hypertrophy and heart fail- (Supplementary Fig. S1). Therefore, it gives rise to the hypothesis that artificial modulation of NAD levels may be used to regulate the function of sirtuins including SIRT6. Abbreviations: SIRT, sirtuin; NAD, nicotinamide adenine dinucleotide; Nmnat, nicotinamide mononucleotide adenylyltransferase; Ang II, angiotensin II; HDACs, In mammalian cells, the biosynthesis of NAD occurs through histone deacetylases; Nampt, nicotinamide phosphoribosyltransferase; AAC, both salvage and de novo pathways [10]. Nicotinamide phosphori- abdominal aortic constriction; ANF, atrial natriuretic factor; BNP, brain natriuretic bosyltransferase (Nampt) is the rate-limiting enzyme for NAD sal- polypeptide; b-MHC, myosin heavy chain b vage from nicotinamide. Previous study has demonstrated that ⇑ Corresponding authors. Fax: +86 20 3994 3026. overexpression of Nampt significantly increased NAD synthesis in E-mail addresses: [email protected] (J.-T. Ye), [email protected] (P.-Q. Liu). primary cultures cardiomyocytes [11]. However, it was reported 1 These authors contributed equally to this work. that overexpression of Nampt in cardiomyocytes stimulates 0014-5793/$36.00 Ó 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2012.02.014 Y. Cai et al. / FEBS Letters 586 (2012) 866–874 867 Fig. 1. Tissue distribution and age-dependent expression of Nmnat2 in rats. The mRNA (A) and protein (B) expression of Nmnat2 in different tissues of SD rats were detected by qRT-PCR and Western blot, respectively. The mRNA expressions of Nmnat isoforms and Nmnat2 protein level in rat hearts at indicated ages were also determined (C and D). ⁄P < 0.05, ⁄⁄P < 0.01 vs. 1d group, n =6. neither Akt/p70S6K signaling in vitro nor cardiac hypertrophy mutant (H24D) plasmids were purchased from LAND Company. in vivo [12]. Nmnat is another central enzyme in NAD synthesis Plasmids were transfected into cells using Lipofectamine 2000 pathway, which catalyzes both de novo and salvage pathways of (Invitrogen) according to the manufacturer’s protocol. NAD synthesis [13]. Up to now, three Nmnat isoforms have been Additional materials and methods including echocardiography identified in mammals which showed differences in subcellular and morphometric measures, quantitative real-time polymerase localization and tissue distribution [14], but very little is known chain reaction (qRT-PCR), Western blot and immunoprecipitation, about the effects of the Nmnat family members on cardiac func- SIRT6 histone deacetylase activity assay, NAD determination, mea- tion. Among the three Nmnat isoforms, Nmnat2 is reported to be surement of cell surface area, immunofluorescence assay, Nmnat2 most sensitive to NAD and can act as a sensor to intracellular enzyme activity assay and RNA interference are listed in Supple- NAD level [13], which might partly explain the facts that high lev- mentary data. Data are presented as mean ± S.E. Statistical analyses els of Nmnat2 are detected in the organs with high demand for en- between two groups were performed by unpaired Student’s t-test. ergy such as heart, brain and skeletal muscle [14]. Using a positive Differences among groups were tested by one-way analysis of var- screen, we have identified that the mRNA level of Nmnat2, but not iance (ANOVA) with Tukey’s post hoc test. In all cases, differences Nmnat1 and Nmnat3, is significantly upregulated in response to were considered statistically significant with P < 0.05. hypertrophic stimulation. However, to our best knowledge, there are no investigations on the potential roles of Nmnat2 in cardiac 3. Results hypertrophy. In this study, by using gain- and loss-of-function approaches in 3.1. Tissue distribution and age-dependent expression of Nmnat2 in cardiomyocytes we show that Nmnat2 is a negative regulator of rats cardiac hypertrophy. Our results also reveal that the anti-hypertro- phic effect of Nmnat2 is dependent on its NAD synthesis activity As shown in Fig. 1A and B, Nmnat2 was highly expressed in and is possibly mediated via activation of SIRT6. These findings liver, heart, brain and muscle, while it could hardly be detected give the first look into the relationship between Nmnat2 and in spleen, lung, kidney and testis. We further investigated the SIRT6-mediated cardioprotection, and may provide a potentially expression of Nmnat isoforms in hearts of rats at indicated ages. novel strategy against cardiac hypertrophy by modulating Nmnat2. The results showed that the mRNA and protein expression of Nmnat2 (Fig. 1C and D) was increased in an age-dependent man- 2. Materials and methods ner, which reached peak at 12 weeks (P < 0.01, compared with 1d group). In contrast, the expression of Nmnat1 and Nmnat3 showed SD rats (male, weighing 180–200 g, SPF grade, certification No. no significant age-related changes. 0067950) were supplied by the Experimental Animal Center of Sun Yat-Sen University (Guangzhou, China). Pressure overload 3.2. Expression and NAD synthase activity of Nmnat2 in neonatal rat was induced by abdominal aortic constriction (AAC) according to cardiomyocytes treated with Ang II procedure reported by others [15]. Primary cultures of neonatal rat cardiomyocytes were prepared as we previously described Ang II is an well-established neurohumoral factor that can stim- [16]. The EGFP-Nmnat2 (Nmnat2) and the catalytically inactive ulate cardiac hypertrophy [17]. As shown in Fig. 2A, the mRNA 868 Y. Cai et al. / FEBS Letters 586 (2012) 866–874 Fig. 2. The protein expression and NAD synthase activity of Nmnat2 was decreased in neonatal rat cardiomyocytes treated with Ang II. (A) The mRNA levels of Nmnat isoforms were determined by qRT-PCR after treatment with 100 nM Ang II for 24 h. The time and concentration-dependent effect of Ang II on Nmnat2 mRNA and protein expression was detected
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