title: Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction.
abstract: Cardiac metabolic remodeling is a central event during heart failure (HF) development following myocardial infarction (MI). It is well known that myocardial glucose and fatty acid dysmetabolism contribute to post-MI cardiac dysfunction and remodeling. However, the role of amino acid metabolism in post-MI HF remains elusive. Branched chain amino acids (BCAAs) are an important group of essential amino acids and function as crucial nutrient signaling in mammalian animals. The present study aimed to determine the role of cardiac BCAA metabolism in post-MI HF progression. Utilizing coronary artery ligation-induced murine MI models, we found that myocardial BCAA catabolism was significantly impaired in response to permanent MI, therefore leading to an obvious elevation of myocardial BCAA abundance. In MI-operated mice, oral BCAA administration further increased cardiac BCAA levels, activated the mammalian target of rapamycin (mTOR) signaling, and exacerbated cardiac dysfunction and remodeling. These data demonstrate that BCAAs act as a direct contributor to post-MI cardiac pathologies. Furthermore, these BCAA-mediated deleterious effects were improved by rapamycin cotreatment, revealing an indispensable role of mTOR in BCAA-mediated adverse effects on cardiac function/structure post-MI. Of note, pharmacological inhibition of branched chain ketoacid dehydrogenase kinase (BDK), a negative regulator of myocardial BCAA catabolism, significantly improved cardiac BCAA catabolic disorders, reduced myocardial BCAA levels, and ameliorated post-MI cardiac dysfunction and remodeling. In conclusion, our data provide the evidence that impaired cardiac BCAA catabolism directly contributes to post-MI cardiac dysfunction and remodeling. Moreover, improving cardiac BCAA catabolic defects may be a promising therapeutic strategy against post-MI HF.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Fuyang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Shihao
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Helin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Congye
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Kun
authors.initials: K
authors.lastname: Lian
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and lingtao@fmmu.edu.cn.
authors.forename: Hexiang
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; and.
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D003331:Coronary Vessels / Q000601:surgery; D004452:Echocardiography; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008026:Ligation; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D000071636:Protein Phosphatase 2C / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism*; D020257:Ventricular Remodeling
chemical_list: D000597:Amino Acids, Branched-Chain; D005227:Fatty Acids; D020097:Natriuretic Peptide, Brain; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase; C000607456:PPM1A protein, human; D000071636:Protein Phosphatase 2C; D005947:Glucose
keywords: branched chain amino acids; heart failure; mammalian target of rapamycin; myocardial infarction; remodeling