title: Monocyte-derived extracellular Nampt-dependent biosynthesis of NAD(+) protects the heart against pressure overload.
abstract: Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step in the salvage pathway for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, and thereby regulates the deacetylase activity of sirtuins. Here we show accommodative regulation of myocardial NAD(+) by monocyte-derived extracellular Nampt (eNampt), which is essential for hemodynamic compensation to pressure overload. Although intracellular Nampt (iNampt) expression was decreased in pressure-overloaded hearts, myocardial NAD(+) concentration and Sirt1 activity were preserved. In contrast, iNampt was up-regulated in spleen and monocytes, and circulating eNampt protein and nicotinamide mononucleotide (NMN), a key precursor of NAD(+), were significantly increased. Pharmacological inhibition of Nampt by FK866 or depletion of monocytes/macrophages by clodronate liposomes disrupted the homeostatic mechanism of myocardial NAD(+) levels and NAD(+)-dependent Sirt1 activity, leading to susceptibility to cardiomyocyte apoptosis and cardiac decompensation in pressure-overloaded mice. These biochemical and hemodynamic defects were prevented by systemic administration of NMN. Our studies uncover a crucial role of monocyte-derived eNampt in myocardial adaptation to pressure overload, and highlight a potential intervention controlling myocardial NAD(+) against heart failure.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Yano
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Oka
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.|Clinical Pharmacy Education Unit, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Chizuru
authors.initials: C
authors.lastname: Yabumoto
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kudo-Sakamoto
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kamo
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yagi
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.|Department of Cardiovascular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Atsuhiko T
authors.initials: AT
authors.lastname: Naito
authors.affiliation: Department of Cardiovascular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, The University of Tokyo, Bunkkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Suzuki
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D006321:Heart / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009243:NAD / Q000096:biosynthesis* / Q000378:metabolism*; D009537:Nicotinamide Mononucleotide / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D020011:Protective Agents / Q000138:chemical synthesis* / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016207:Cytokines; D020011:Protective Agents; D009243:NAD; D009537:Nicotinamide Mononucleotide; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D056564:Sirtuin 1