Cardiac Molecular Analysis Reveals Aging-Associated Metabolic Alterations Promoting Glycosaminoglycans Accumulation via Hexosamine Biosynthetic Pathway.

Autor: Grilo LF; CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3060, Portugal.; CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, 3060, Portugal.; Institute for Interdisciplinary Research, PDBEB - Doctoral Programme in Experimental Biology and Biomedicine, University of Coimbra, Coimbra, 3060, Portugal.; Center for Precision Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA., Zimmerman KD; Center for Precision Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA.; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA., Puppala S; Center for Precision Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA.; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA., Chan J; Center for Precision Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA.; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA., Huber HF; Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, 78245, USA., Li G; Center for Precision Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA., Jadhav AYL; Center for Precision Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA., Wang B; Center for Precision Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA., Li C; Texas Pregnancy & Life-Course Health Research Center, Department of Animal Science, University of Wyoming, Laramie, WY, 82071, USA., Clarke GD; Department of Radiology, University of Texas Health Science Center, San Antonio, TX, 78229, USA., Register TC; Center for Precision Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA.; Section on Comparative Medicine, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA., Oliveira PJ; CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3060, Portugal.; CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, 3060, Portugal., Nathanielsz PW; Texas Pregnancy & Life-Course Health Research Center, Department of Animal Science, University of Wyoming, Laramie, WY, 82071, USA., Olivier M; Center for Precision Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA.; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA., Pereira SP; CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3060, Portugal.; CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, 3060, Portugal.; Laboratory of Metabolism and Exercise (LaMetEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Laboratory for Integrative and Translational Research in Population Health (ITR), Faculty of Sports, University of Porto, Porto, 4050, Portugal., Cox LA; Center for Precision Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA.; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.; Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, 78245, USA.; Section on Comparative Medicine, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Oct; Vol. 11 (38), pp. e2309211. Date of Electronic Publication: 2024 Aug 09.
DOI: 10.1002/advs.202309211
Abstrakt: Age is a prominent risk factor for cardiometabolic disease, often leading to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction exclusively resulting from physiological aging remain elusive. Previous research demonstrated age-related functional alterations in baboons, analogous to humans. The goal of this study is to identify early cardiac molecular alterations preceding functional adaptations, shedding light on the regulation of age-associated changes. Unbiased transcriptomics of left ventricle samples are performed from female baboons aged 7.5-22.1 years (human equivalent ≈30-88 years). Weighted-gene correlation network and pathway enrichment analyses are performed, with histological validation. Modules of transcripts negatively correlated with age implicated declined metabolism-oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid β-oxidation. Transcripts positively correlated with age suggested a metabolic shift toward glucose-dependent anabolic pathways, including hexosamine biosynthetic pathway (HBP). This shift is associated with increased glycosaminoglycan synthesis, modification, precursor synthesis via HBP, and extracellular matrix accumulation, verified histologically. Upregulated extracellular matrix-induced signaling coincided with glycosaminoglycan accumulation, followed by cardiac hypertrophy-related pathways. Overall, these findings revealed a transcriptional shift in metabolism favoring glycosaminoglycan accumulation through HBP before cardiac hypertrophy. Unveiling this metabolic shift provides potential targets for age-related cardiac diseases, offering novel insights into early age-related mechanisms.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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