Adrenergic stress reveals septal hypertrophy and proteasome impairment in heterozygous Mybpc3-targeted knock-in mice
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Adrenergic stress reveals septal hypertrophy and proteasome impairment in heterozygous Mybpc3-targeted knock-in mice. / Schlossarek, Saskia; Schürmann, Friederike; Geertz, Birgit; Mearini, Giulia; Eschenhagen, Thomas; Carrier, Lucie.
in: J MUSCLE RES CELL M, Jahrgang 33, Nr. 1, 01.05.2012, S. 5-15.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Adrenergic stress reveals septal hypertrophy and proteasome impairment in heterozygous Mybpc3-targeted knock-in mice
AU - Schlossarek, Saskia
AU - Schürmann, Friederike
AU - Geertz, Birgit
AU - Mearini, Giulia
AU - Eschenhagen, Thomas
AU - Carrier, Lucie
PY - 2012/5/1
Y1 - 2012/5/1
N2 - Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric septal hypertrophy and is often caused by mutations in MYBPC3 gene encoding cardiac myosin-binding protein C. In contrast to humans, who are already affected at the heterozygous state, mouse models develop the phenotype mainly at the homozygous state. Evidence from cell culture work suggested that altered proteasome function contributes to the pathogenesis of HCM. Here we tested in two heterozygous Mybpc3-targeted mouse models whether adrenergic stress unmasks a specific cardiac phenotype and proteasome dysfunction. The first model carries a human Mybpc3 mutation (Het-KI), the second is a heterozygous Mybpc3 knock-out (Het-KO). Both models were compared to wild-type (WT) mice. Mice were treated with a combination of isoprenaline and phenylephrine (ISO/PE) or NaCl for 1 week. Whereas ISO/PE induced left ventricular hypertrophy (LVH) with increased posterior wall thickness to a similar extent in all groups, it increased septum thickness only in Het-KI and Het-KO. ISO/PE did not affect the proteasomal chymotrypsin-like activity or β5-subunit protein level in Het-KO or wild-type mice (WT). In contrast, both parameters were markedly lower in Het-KI and negatively correlated with the degree of LVH in Het-KI only. In conclusion, adrenergic stress revealed septal hypertrophy in both heterozygous mouse models of HCM, but proteasome dysfunction only in Het-KI mice, which carry a mutant allele and closely mimic human HCM. This supports the hypothesis that proteasome impairment contributes to the pathophysiology of HCM.
AB - Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric septal hypertrophy and is often caused by mutations in MYBPC3 gene encoding cardiac myosin-binding protein C. In contrast to humans, who are already affected at the heterozygous state, mouse models develop the phenotype mainly at the homozygous state. Evidence from cell culture work suggested that altered proteasome function contributes to the pathogenesis of HCM. Here we tested in two heterozygous Mybpc3-targeted mouse models whether adrenergic stress unmasks a specific cardiac phenotype and proteasome dysfunction. The first model carries a human Mybpc3 mutation (Het-KI), the second is a heterozygous Mybpc3 knock-out (Het-KO). Both models were compared to wild-type (WT) mice. Mice were treated with a combination of isoprenaline and phenylephrine (ISO/PE) or NaCl for 1 week. Whereas ISO/PE induced left ventricular hypertrophy (LVH) with increased posterior wall thickness to a similar extent in all groups, it increased septum thickness only in Het-KI and Het-KO. ISO/PE did not affect the proteasomal chymotrypsin-like activity or β5-subunit protein level in Het-KO or wild-type mice (WT). In contrast, both parameters were markedly lower in Het-KI and negatively correlated with the degree of LVH in Het-KI only. In conclusion, adrenergic stress revealed septal hypertrophy in both heterozygous mouse models of HCM, but proteasome dysfunction only in Het-KI mice, which carry a mutant allele and closely mimic human HCM. This supports the hypothesis that proteasome impairment contributes to the pathophysiology of HCM.
KW - Adrenergic alpha-Agonists
KW - Adrenergic beta-Agonists
KW - Alleles
KW - Animals
KW - Cardiomyopathy, Hypertrophic
KW - Carrier Proteins
KW - Cytosol
KW - Echocardiography
KW - Gene Knock-In Techniques
KW - Gene Transfer Techniques
KW - Heterozygote
KW - Homologous Recombination
KW - Humans
KW - Hypertrophy, Left Ventricular
KW - Isoproterenol
KW - Mice
KW - Mice, Transgenic
KW - Mutation
KW - Phenotype
KW - Phenylephrine
KW - Proteasome Endopeptidase Complex
KW - Sodium Chloride
KW - Stress, Physiological
U2 - 10.1007/s10974-011-9273-6
DO - 10.1007/s10974-011-9273-6
M3 - SCORING: Journal article
C2 - 22076249
VL - 33
SP - 5
EP - 15
JO - J MUSCLE RES CELL M
JF - J MUSCLE RES CELL M
SN - 0142-4319
IS - 1
ER -