title: Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis.
abstract: Familial hypertrophic cardiomyopathy (FHC) is a disease caused by mutations in contractile proteins of the sarcomere. Our laboratory developed a mouse model of FHC with a mutation in the thin filament protein alpha-tropomyosin (TM) at amino acid 180 (Glu180Gly). The hearts of these mice exhibit dramatic systolic and diastolic dysfunction, and their myofilaments demonstrate increased calcium sensitivity. The mice also develop severe cardiac hypertrophy, with death ensuing by 6 mo. In an attempt to normalize calcium sensitivity in the cardiomyofilaments of the hypertrophic mice, we generated a chimeric alpha-/beta-TM protein that decreases calcium sensitivity in transgenic mouse cardiac myofilaments. By mating mice from these two models together, we tested the hypothesis that an attenuation of myofilament calcium sensitivity would modulate the severe physiological and pathological consequences of the FHC mutation. These double-transgenic mice "rescue" the hypertrophic phenotype by exhibiting a normal morphology with no pathological abnormalities. Physiological analyses of these rescued mice show improved cardiac function and normal myofilament calcium sensitivity. These results demonstrate that alterations in calcium response by modification of contractile proteins can prevent the pathological and physiological effects of this disease.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, USA.
authors.forename: Ganapathy
authors.initials: G
authors.lastname: Jagatheesan
authors.forename: Sudarsan
authors.initials: S
authors.lastname: Rajan
authors.forename: Natalia
authors.initials: N
authors.lastname: Petrashevskaya
authors.forename: Arnold
authors.initials: A
authors.lastname: Schwartz
authors.forename: Greg
authors.initials: G
authors.lastname: Boivin
authors.forename: Grace M
authors.initials: GM
authors.lastname: Arteaga
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
authors.forename: David F
authors.initials: DF
authors.lastname: Wieczorek
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005838:Genotype; D006339:Heart Rate; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism*; D017725:Ventricular Pressure
chemical_list: D000318:Adrenergic beta-Agonists; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C490774:Tpm1 protein, mouse; D014335:Tropomyosin; D007545:Isoproterenol; D002118:Calcium