Abstract 1234: Proteomic Analysis Provides Insights into Molecular Mechanisms of Atrial Profibrillatory Remodeling in Congestive Heart Failure
Congestive heart failure (CHF) leads to atrial structural remodeling and increased susceptibility to sustained atrial fibrillation (AF). The underlying molecular mechanisms are poorly understood.
Objective and Methods: To assess the broad range of atrial protein changes in CHF, we applied high-throughput proteomic analysis to left atrial cardiomyocytes harvested from sham (n = 5) and ventricular-tachypaced (VTP, 240 bpm × 2 wks, n = 4) CHF dogs. Protein extracts were subjected to two-dimensional gel electrophoresis (2-DE) using differential in-gel electrophoresis technology. Differentially expressed proteins (p < 0.05) were excised for identification via tandem mass spectrometry.
Results: From our protein extracts, 1103 proteins were resolved using 2-DE, and 225 proteins were significantly altered between the groups (132 increased, 93 decreased in VTP). To date, 115 of these have been identified by mass spectrometry. Among the significantly upregulated atrial proteins in CHF were heat shock proteins (HSPs: α-B crystallin, HSP70 and GRP78) and numerous extracellular matrix (ECM) associated proteins (including desmin, filamin C, tubulin and vimentin). Downregulated proteins included antioxidants (superoxide dismutase, peroxiredoxin 3 and selenium-binding protein), structural proteins (myosin light chains 1 and 2 and cardiac troponin T) and key enzymes involved in metabolism (pyruvate dehydrogenase E1 component α subunit, citrate lyase beta like, malate dehydrogenase, isocitrate dehydrogenase 1, H+ transporting ATP synthase mitochondrial F0 complex and ubiquinol-cytochrome C reductase core protein 1).
Conclusions: VTP-induced CHF substantially alters the atrial protein expression profile. Upregulated ECM proteins account for AF-promoting fibrosis while HSPs may reflect autoprotective mechanisms. Downregulated contractile proteins likely account for thrombosis-promoting stunning, antioxidants reflect oxidative stress, and decreased metabolic proteins suggest adaptations to increased metabolic needs. This first large scale proteomic analysis of CHF-induced atrial remodeling provides novel insights into molecular mechanisms underlying an atrial remodeling paradigm of substantial clinical relevance.