Khanh V Doan,Timothy S Luongo,Thato T Ts'olo,Won Dong Lee,David W Frederick,Sarmistha Mukherjee,Gabriel K Adzika,Caroline E Perry,Ryan B Gaspar,Nicole Walker,Megan C Blair,Nicole Bye,James G Davis,Corey D Holman,Qingwei Chu,Lin Wang,Joshua D Rabinowitz,Daniel P Kelly,Thomas P Cappola,Kenneth B Margulies,Joseph A Baur
{"title":"Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.","authors":"Khanh V Doan,Timothy S Luongo,Thato T Ts'olo,Won Dong Lee,David W Frederick,Sarmistha Mukherjee,Gabriel K Adzika,Caroline E Perry,Ryan B Gaspar,Nicole Walker,Megan C Blair,Nicole Bye,James G Davis,Corey D Holman,Qingwei Chu,Lin Wang,Joshua D Rabinowitz,Daniel P Kelly,Thomas P Cappola,Kenneth B Margulies,Joseph A Baur","doi":"10.1038/s44161-024-00542-9","DOIUrl":null,"url":null,"abstract":"Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":null,"pages":null},"PeriodicalIF":9.4000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature cardiovascular research","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/s44161-024-00542-9","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.