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Tachycardia-induced metabolic rewiring as a driver of contractile dysfunction.
Tu, Chengyi; Caudal, Arianne; Liu, Yu; Gorgodze, Nikoloz; Zhang, Hao; Lam, Chi Keung; Dai, Yuqin; Zhang, Angela; Wnorowski, Alexa; Wu, Matthew A; Yang, Huaxiao; Abilez, Oscar J; Lyu, Xuchao; Narayan, Sanjiv M; Mestroni, Luisa; Taylor, Matthew R G; Recchia, Fabio A; Wu, Joseph C.
Afiliación
  • Tu C; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Caudal A; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Liu Y; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Gorgodze N; Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
  • Zhang H; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Lam CK; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Dai Y; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • Zhang A; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Wnorowski A; Greenstone Biosciences, Palo Alto, CA, USA.
  • Wu MA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Yang H; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Abilez OJ; Greenstone Biosciences, Palo Alto, CA, USA.
  • Lyu X; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Narayan SM; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Mestroni L; Department of Pathology, Stanford University, Stanford, CA, USA.
  • Taylor MRG; Department of Medicine, Stanford University, Stanford, CA, USA.
  • Recchia FA; Human Medical Genetics and Genomics, University of Colorado, Aurora, CO, USA.
  • Wu JC; Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA.
Nat Biomed Eng ; 2023 Nov 27.
Article en En | MEDLINE | ID: mdl-38012305
ABSTRACT
Prolonged tachycardia-a risk factor for cardiovascular morbidity and mortality-can induce cardiomyopathy in the absence of structural disease in the heart. Here, by leveraging human patient data, a canine model of tachycardia and engineered heart tissue generated from human induced pluripotent stem cells, we show that metabolic rewiring during tachycardia drives contractile dysfunction by promoting tissue hypoxia, elevated glucose utilization and the suppression of oxidative phosphorylation. Mechanistically, a metabolic shift towards anaerobic glycolysis disrupts the redox balance of nicotinamide adenine dinucleotide (NAD), resulting in increased global protein acetylation (and in particular the acetylation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase), a molecular signature of heart failure. Restoration of NAD redox by NAD+ supplementation reduced sarcoplasmic/endoplasmic reticulum Ca2+-ATPase acetylation and accelerated the functional recovery of the engineered heart tissue after tachycardia. Understanding how metabolic rewiring drives tachycardia-induced cardiomyopathy opens up opportunities for therapeutic intervention.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nat Biomed Eng Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nat Biomed Eng Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos