Multi-Omics Approach Profiling Metabolic Remodeling in Early Systolic Dysfunction and in Overt Systolic Heart Failure

International Journal of Molecular Sciences

Todd Markowski¹  LeeAnn Higgins¹  Charles Burant²  Patrice Delafontaine³  Antoine H. Chaanine³  Jarrod Harman⁴  David Busija⁵  L. Gabriel Navar⁶  Maureen Kachman⁷ 

[1] Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA;Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA;Department of Medicine, Tulane University, New Orleans, LA 70112, USA;Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA;Department of Pharmacology, Tulane University, New Orleans, LA 70112, USA;Department of Physiology, Tulane University, New Orleans, LA 70112, USA;Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI 48109, USA;

关键词: heart failure;    metabolic remodeling;    mitochondria;    PKA;    AMPK;    calcium cycling;   

DOI  :  10.3390/ijms23010235

来源: DOAJ

【 摘 要 】

Metabolic remodeling plays an important role in the pathophysiology of heart failure (HF). We sought to characterize metabolic remodeling and implicated signaling pathways in two rat models of early systolic dysfunction (MOD), and overt systolic HF (SHF). Tandem mass tag-labeled shotgun proteomics, phospho-(p)-proteomics, and non-targeted metabolomics analyses were performed in left ventricular myocardium tissue from Sham, MOD, and SHF using liquid chromatography–mass spectrometry, n = 3 biological samples per group. Mitochondrial proteins were predominantly down-regulated in MOD (125) and SHF (328) vs. Sham. Of these, 82% (103/125) and 66% (218/328) were involved in metabolism and respiration. Oxidative phosphorylation, mitochondrial fatty acid β-oxidation, Krebs cycle, branched-chain amino acids, and amino acid (glutamine and tryptophan) degradation were highly enriched metabolic pathways that decreased in SHF > MOD. Glycogen and glucose degradation increased predominantly in MOD, whereas glycolysis and pyruvate metabolism decreased predominantly in SHF. PKA signaling at the endoplasmic reticulum–mt interface was attenuated in MOD, whereas overall PKA and AMPK cellular signaling were attenuated in SHF vs. Sham. In conclusion, metabolic remodeling plays an important role in myocardial remodeling. PKA and AMPK signaling crosstalk governs metabolic remodeling in progression to SHF.

【 授权许可】

Unknown