title: Akt signaling pathway in pacing-induced heart failure.
abstract: Marked changes in energy substrate utilization occur during the progression of congestive heart failure (CHF) where fatty acid utilization, as the primary source of cardiac energy, is severely diminished, oxidative phosphorylation is down-regulated, and glucose uptake and utilization increase. Neither the signaling events or the molecular basis for the shift in substrate utilization have yet been elucidated. This study was designed to examine in the canine model of paced-induced CHF, the potential role of the Akt pathway in signaling the metabolic transitions central to progression to heart failure. Myocardial Akt levels were elevated in early heart failure (after 1-2 weeks of pacing) accompanied by increased levels of oxidative stress, cytokine tumor necrosis factor-alpha (TNF-alpha) and free fatty acid accumulation, reduced activity levels of mitochondrial respiratory complexes III and V and apoptosis initiation. At severe heart failure (3-4 weeks of pacing), there was significant further increase in myocardial apoptosis, with pronounced decline in myocardial Akt kinase activity. At this later stage, there were no further changes in free fatty acid accumulation, complex V activity or in oxidative stress levels indicating that these changes primarily occurred in the earlier stage of evolving heart failure. In contrast, during severe heart failure, both the reduction in complex III activity and increase in TNF-alpha level became more pronounced. Our data provide critical support for the hypothesis that the Akt signaling pathway is a contributory element in the early signaling events leading to the progression of pacing-induced heart failure, accompanying the shift in substrate utilization.
authors.affiliation: The Molecular Cardiology and Neuromuscular Institute, Highland Park, NJ 08904, USA.
authors.forename: Radha
authors.initials: R
authors.lastname: Ananthakrishnan
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Moe
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goldenthal
authors.forename: José
authors.initials: J
authors.lastname: Marín-García
mesh_terms: D000818:Animals; D017209:Apoptosis; D004285:Dogs; D014450:Electron Transport Complex III / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006333:Heart Failure / Q000503:physiopathology*; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D005227:Fatty Acids; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D014450:Electron Transport Complex III
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