title: Physiological growth synergizes with pathological genes in experimental cardiomyopathy.
abstract: Hundreds of signaling molecules have been assigned critical roles in the pathogenesis of myocardial hypertrophy and heart failure based on cardiac phenotypes from alpha-myosin heavy chain-directed overexpression mice. Because permanent ventricular transgene expression in this system begins during a period of rapid physiological neonatal growth, resulting phenotypes are the combined consequences of transgene effects and normal trophic influences. We used temporally-defined forced gene expression to investigate synergy between postnatal physiological cardiac growth and two functionally divergent cardiomyopathic genes. Phenotype development was compared various times after neonatal (age 2 to 3 days) and adult (age 8 weeks) expression. Proapoptotic Nix caused ventricular dilation and severe contractile depression in neonates, but not adults. Myocardial apoptosis was minimal in adults, but was widespread in neonates, until it spontaneously resolved in adulthood. Unlike normal postnatal cardiac growth, concurrent left ventricular pressure overload hypertrophy did not synergize with Nix expression to cause cardiomyopathy or myocardial apoptosis. Prohypertrophic Galphaq likewise caused eccentric hypertrophy, systolic dysfunction, and pathological gene expression in neonates, but not adults. Thus, normal postnatal cardiac growth can be an essential cofactor in development of genetic cardiomyopathies, and may confound the interpretation of conventional alpha-MHC transgenic phenotypes.
authors.affiliation: Heart and Vascular Center of the University of Cincinnati, Ohio 45267-0542, USA.
authors.forename: Faisal
authors.initials: F
authors.lastname: Syed
authors.forename: Amy
authors.initials: A
authors.lastname: Odley
authors.forename: Harvey S
authors.initials: HS
authors.lastname: Hahn
authors.forename: Eric W
authors.initials: EW
authors.lastname: Brunskill
authors.forename: Roy A
authors.initials: RA
authors.lastname: Lynch
authors.forename: Yehia
authors.initials: Y
authors.lastname: Marreez
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001017:Aortic Coarctation / Q000150:complications; D017209:Apoptosis; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003433:Crosses, Genetic; D004318:Doxycycline / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006321:Heart / Q000254:growth & development*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics*; D008969:Molecular Sequence Data; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D019076:Transgenes / Q000187:drug effects
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C501741:Nix protein, mouse; D011993:Recombinant Fusion Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D004318:Doxycycline