title: In vivo natriuretic peptide reporter assay identifies chemical modifiers of hypertrophic cardiomyopathy signalling.
abstract: OBJECTIVE
  Despite increased understanding of the fundamental biology regulating cardiomyocyte hypertrophy and heart failure, it has been challenging to find novel chemical or genetic modifiers of these pathways. Traditional cell-based methods do not model the complexity of an intact cardiovascular system and mammalian models are not readily adaptable to chemical or genetic screens. Our objective was to create an in vivo model suitable for chemical and genetic screens for hypertrophy and heart failure modifiers.
  
  
  RESULTS
  Using the developing zebrafish, we established that the cardiac natriuretic peptide genes (nppa and nppb), known markers of cardiomyocyte hypertrophy and heart failure, were induced in the embryonic heart by pathological cardiac stimuli. This pathological induction was distinct from the developmental regulation of these genes. We created a luciferase-based transgenic reporter line that accurately modelled the pathological induction patterns of the zebrafish nppb gene. Utilizing this reporter line, we were able to show remarkable conservation of pharmacological responses between the larval zebrafish heart and adult mammalian models.
  
  
  CONCLUSIONS
  By performing a focused screen of chemical agents, we were able to show a distinct response of a genetic model of hypertrophic cardiomyopathy to the histone deacetylase inhibitor, Trichostatin A, and the mitogen-activated protein kinase kinase 1/2 inhibitor, U0126. We believe this in vivo reporter line will offer a unique approach to the identification of novel chemical or genetic regulators of myocardial hypertrophy and heart failure.
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2220 Pierce Avenue, 340 PRB, Nashville, TN 37232-6300, USA. jason.becker@vanderbilt.edu
authors.forename: Jason R
authors.initials: JR
authors.lastname: Becker
authors.forename: Tamara Y
authors.initials: TY
authors.lastname: Robinson
authors.forename: Chetana
authors.initials: C
authors.lastname: Sachidanandan
authors.forename: Amy E
authors.initials: AE
authors.lastname: Kelly
authors.forename: Shannon
authors.initials: S
authors.lastname: Coy
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002070:Butadienes / Q000494:pharmacology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D017930:Genes, Reporter / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics*; D008322:Mammals; D045265:Natriuretic Peptides / Q000235:genetics* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D005819:Genetic Markers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D045265:Natriuretic Peptides; D009570:Nitriles; C113580:U 0126; C012589:trichostatin A; D008156:Luciferases