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Am J Physiol Heart Circ Physiol ; 284(2): H575-83, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12414446

RESUMO

Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by varying degrees of ventricular hypertrophy and myofibrillar disarray. Mutations in cardiac contractile proteins cause HCM. However, there is an unexplained wide variability in the clinical phenotype, and it is likely that there are multiple contributing factors. Because mitochondrial dysfunction has been described in heart disease, we tested the hypothesis that mitochondrial dysfunction contributes to the varying HCM phenotypes. Mitochondrial function was assessed in two transgenic models of HCM: mice with a mutant myosin heavy chain gene (MyHC) or with a mutant cardiac troponin T (R92Q) gene. Despite mitochondrial ultrastructural abnormalities in both models, the rate of state 3 respiration was significantly decreased only in the mutant MyHC mice by approximately 23%. Notably, this decrease in state 3 respiration preceded hemodynamic dysfunction. The maximum activity of alpha-ketogutarate dehydrogenase as assayed in isolated disrupted mitochondria was decreased by 28% compared with isolated control mitochondria. In addition, complexes I and IV were decreased in mutant MyHC transgenic mice. Inhibition of beta-adrenergic receptor kinase, which is elevated in mutant MyHC mouse hearts, can prevent mitochondrial respiratory impairment in mutant MyHC mice. Thus our results suggest that mitochondria may contribute to the hemodynamic dysfunction seen in some forms of HCM and offer a plausible mechanism responsible for some of the heterogeneity of the disease phenotypes.


Assuntos
Cardiomiopatia Hipertrófica/fisiopatologia , Mitocôndrias Cardíacas/fisiologia , Animais , Cardiomiopatia Hipertrófica/patologia , Complexo I de Transporte de Elétrons , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hemodinâmica , Hibridização Genética , Complexo Cetoglutarato Desidrogenase/metabolismo , Camundongos , Camundongos Mutantes , Camundongos Transgênicos/genética , Mitocôndrias Cardíacas/ultraestrutura , Cadeias Pesadas de Miosina/genética , NADH NADPH Oxirredutases/metabolismo , Consumo de Oxigênio , Troponina T/genética
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