title: Integrated Omic Analysis of a Guinea Pig Model of Heart Failure and Sudden Cardiac Death.
abstract: Here, we examine key regulatory pathways underlying the transition from compensated hypertrophy (HYP) to decompensated heart failure (HF) and sudden cardiac death (SCD) in a guinea pig pressure-overload model by integrated multiome analysis. Relative protein abundances from sham-operated HYP and HF hearts were assessed by iTRAQ LC-MS/MS. Metabolites were quantified by LC-MS/MS or GC-MS. Transcriptome profiles were obtained using mRNA microarrays. The guinea pig HF proteome exhibited classic biosignatures of cardiac HYP, left ventricular dysfunction, fibrosis, inflammation, and extravasation. Fatty acid metabolism, mitochondrial transcription/translation factors, antioxidant enzymes, and other mitochondrial procsses, were downregulated in HF but not HYP. Proteins upregulated in HF implicate extracellular matrix remodeling, cytoskeletal remodeling, and acute phase inflammation markers. Among metabolites, acylcarnitines were downregulated in HYP and fatty acids accumulated in HF. The correlation of transcript and protein changes in HF was weak (R(2) = 0.23), suggesting post-transcriptional gene regulation in HF. Proteome/metabolome integration indicated metabolic bottlenecks in fatty acyl-CoA processing by carnitine palmitoyl transferase (CPT1B) as well as TCA cycle inhibition. On the basis of these findings, we present a model of cardiac decompensation involving impaired nuclear integration of Ca(2+) and cyclic nucleotide signals that are coupled to mitochondrial metabolic and antioxidant defects through the CREB/PGC1α transcriptional axis.
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: D Brian
authors.initials: DB
authors.lastname: Foster
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland 21205, United States.
authors.forename: Kai
authors.initials: K
authors.lastname: Kammers
authors.affiliation: Proteomics Core Facility, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: O'Meally
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Ni
authors.initials: N
authors.lastname: Yang
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Kyriakos N
authors.initials: KN
authors.lastname: Papanicolaou
authors.affiliation: Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: C Conover
authors.initials: CC
authors.lastname: Talbot
authors.affiliation: Proteomics Core Facility, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Cole
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism; D002952:Citric Acid Cycle; D016757:Death, Sudden, Cardiac; D004195:Disease Models, Animal; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism; D006168:Guinea Pigs; D006333:Heart Failure / Q000378:metabolism*; D006973:Hypertension / Q000150:complications; D050356:Lipid Metabolism; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D040901:Proteomics / Q000379:methods*; D059467:Transcriptome
chemical_list: D005227:Fatty Acids
keywords: heart failure; hypertrophy; mass spectrometry; median sweep; metabolic bottleneck; metabolome; pathway analysis; proteome; proteomics; transcriptome