title: Comparative differential proteomic profiles of nonfailing and failing hearts after in vivo thoracic aortic constriction in mice overexpressing FKBP12.6.
abstract: Chronic pressure overload (PO) induces pathological left ventricular hypertrophy (LVH) leading to congestive heart failure (HF). Overexpression of FKBP12.6 (FK506-binding protein [K]) in mice should prevent Ca2+-leak during diastole and may improve overall cardiac function. In order to decipher molecular mechanisms involved in thoracic aortic constriction (TAC)-induced cardiac remodeling and the influence of gender and genotype, we performed a proteomic analysis using two-dimensional differential in-gel electrophoresis (2D-DIGE), mass spectrometry, and bioinformatics techniques to identify alterations in characteristic biological networks. Wild-type (W) and K mice of both genders underwent TAC. Thirty days post-TAC, the altered cardiac remodeling was accompanied with systolic and diastolic dysfunction in all experimental groups. A gender difference in inflammatory protein expression (fibrinogen, α-1-antitrypsin isoforms) and in calreticulin occurred (males > females). Detoxification enzymes and cytoskeletal proteins were noticeably increased in K mice. Both non- and congestive failing mouse heart exhibited down- and upregulation of proteins related to mitochondrial function and purine metabolism, respectively. HF was characterized by a decrease in enzymes related to iron homeostasis, and altered mitochondrial protein expression related to fatty acid metabolism, glycolysis, and redox balance. Moreover, two distinct differential protein profiles characterized TAC-induced pathological LVH and congestive HF in all TAC mice. FKBP12.6 overexpression did not influence TAC-induced deleterious effects. Huntingtin was revealed as a potential mediator for HF. A broad dysregulation of signaling proteins associated with congestive HF suggested that different sets of proteins could be selected as useful biomarkers for HF progression and might predict outcome in PO-induced pathological LVH.
authors.affiliation: UMR698, INSERM Paris, France.
authors.forename: Miresta
authors.initials: M
authors.lastname: Prévilon
authors.forename: Morgane
authors.initials: M
authors.lastname: Le Gall
authors.forename: Philippe
authors.initials: P
authors.lastname: Chafey
authors.forename: Christian
authors.initials: C
authors.lastname: Federeci
authors.forename: Mylène
authors.initials: M
authors.lastname: Pezet
authors.forename: Guilhem
authors.initials: G
authors.lastname: Clary
authors.forename: Cédric
authors.initials: C
authors.lastname: Broussard
authors.forename: Guillonneau
authors.initials: G
authors.lastname: François
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Mercadier
authors.forename: Patricia
authors.initials: P
authors.lastname: Rouet-Benzineb
keywords: 2D-DIGE; FKBP12.6; Proteomics; cardiac hypertrophy; gender; heart failure; pressure overload; transgenic mice