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Article Dans Une Revue Circulation Research Année : 2022

Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure

Gizem Keceli
  • Fonction : Auteur
Ashish Gupta
  • Fonction : Auteur
Refaat Gabr
  • Fonction : Auteur
Michael Schär
  • Fonction : Auteur
Swati Dey
  • Fonction : Auteur
Carlo Tocchetti
  • Fonction : Auteur
Annina Stuber
  • Fonction : Auteur
Jacopo Agrimi
  • Fonction : Auteur
Yi Zhang
  • Fonction : Auteur
Michelle Leppo
  • Fonction : Auteur
Charles Steenbergen
  • Fonction : Auteur
Shenghan Lai
  • Fonction : Auteur
Lisa Yanek
  • Fonction : Auteur
Brian O’rourke
  • Fonction : Auteur
Gary Gerstenblith
  • Fonction : Auteur
Paul Bottomley
  • Fonction : Auteur
Yibin Wang
  • Fonction : Auteur
Nazareno Paolocci
  • Fonction : Auteur
Robert Weiss
  • Fonction : Auteur

Résumé

Background: Abnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. To test the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF. Methods: First, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance 31P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice. Results: In people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling. Conclusions: In the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00181259.
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Dates et versions

hal-03589691 , version 1 (25-02-2022)

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Gizem Keceli, Ashish Gupta, Joevin Sourdon, Refaat Gabr, Michael Schär, et al.. Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure. Circulation Research, 2022, ⟨10.1161/CIRCRESAHA.121.319648⟩. ⟨hal-03589691⟩
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