Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure
Keceli G, Keceli G, Gupta A, Sourdon J, Gabr R, Schär M, Dey S, Tocchetti CG, Stuber A, Agrimi J, Zhang Y, Leppo M, Steenbergen C, Lai S, Yanek LR, O'Rourke B, Gerstenblith G, Bottomley PA, Wang Y, Paolocci N, Weiss RG
Circulation research · 53 citas
Cómo se estudió
- Diseño
- Estudio en animales (clasificado por nuestro filtro de IA)
- Estudiado en
- Personas, más trabajo en animales o laboratorio
- Resultado principal
- Marcadores de salud y funcionamiento
Quién lo pagó
- Financiación
- Financiación independiente
- Gobierno
- National Institute on Aging
- Gobierno
- National Heart, Lung, and Blood Institute
- Gobierno
- NHLBI NIH HHS
- Gobierno
- NIA NIH HHS
- Subvenciones
- National Heart, Lung, and Blood Institute (R01 HL061912); National Institute on Aging (T32AG058527); National Heart, Lung, and Blood Institute (R01 HL063030); National Institute on Aging (P30 AG021334); National Heart, Lung, and Blood Institute (R01HL134821); National Heart, Lung, and Blood Institute (R01 HL136918)
Según 4 financiadores declarados.
Publicación
- Publicado
- 2022-02-03 · Circ Res · vol. 130 · número 5 · págs. 741–759
- Editorial
- Lippincott Williams & Wilkins
- Citado
- 43 citas · más que el 98% de estudios similares · 6.3× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 74 trabajos
- Acceso
- Lectura gratuita
- Áreas de investigación
- Cardiac Fibrosis and Remodeling · Cardiovascular Function and Risk Factors · Mitochondrial Function and Pathology
- Palabras clave
- Heart failure, Ventricular remodeling, Mitochondrion, Muscle hypertrophy, Energy metabolism, Creatine kinase, Cardiac hypertrophy, Fibrosis
- MeSH
- myocardium, animals, humans, mice, hypertrophy, left ventricular, reactive oxygen species, creatine kinase, adenosine diphosphate, adenosine triphosphate, energy metabolism, ventricular remodeling, creatine kinase, mitochondrial form, heart failure
20 autores
- Gizem Keceli🇺🇸Johns Hopkins University; Johns Hopkins Medicine
- Ashish Gupta🇺🇸Johns Hopkins University; Johns Hopkins Medicine
- Joevin Sourdon🇺🇸Johns Hopkins University; Johns Hopkins Medicine
- Refaat Gabr🇺🇸University of Texas Health Science Center at Dallas; The University of Texas Health Science Center; The University of Texas Health Science Center at Houston
- Michael Schär🇺🇸Johns Hopkins University; Johns Hopkins Medicine
- Swati Dey🇺🇸Vanderbilt University Medical Center
- Carlo G. Tocchetti🇮🇹Federico II University Hospital
- Annina Stuber🇨🇭École Polytechnique Fédérale de Lausanne
- Jacopo Agrimi🇺🇸Johns Hopkins University; Johns Hopkins Medicine
- Yi Zhang🇺🇸Johns Hopkins University; Johns Hopkins Medicine
- Michelle Leppo🇺🇸Johns Hopkins University; Johns Hopkins Medicine
- Charles Steenbergen
- Shenghan Lai🇺🇸University of Maryland, Baltimore; Johns Hopkins University; Johns Hopkins Medicine
- Lisa R. Yanek🇻🇳General Department of Preventive Medicine
- Brian O’Rourke🇺🇸Johns Hopkins University; Johns Hopkins Medicine
- Gary Gerstenblith🇺🇸Johns Hopkins University; Johns Hopkins Medicine
- Paul A. Bottomley🇺🇸Johns Hopkins University; Johns Hopkins Medicine
- Yibin Wang🇺🇸University of California, Los Angeles
- Nazareno Paolocci🇮🇹🇺🇸University of Padua; Johns Hopkins University; Johns Hopkins Medicine
- Robert G. Weiss🇺🇸Johns Hopkins University; Johns Hopkins Medicine
Resumen
El texto original del estudio, en el idioma en que se publicó.
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. We tested 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.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial.
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