Alterations in mitochondrial function in a mouse model of hypertrophic cardiomyopathy
Alterations in mitochondrial function in a mouse model of hypertrophic cardiomyopathy
复制标题
DOI：
10.1152/ajpheart.00619.2002
复制
发表时间：
2003-02-01
影响因子：
4.8
通讯作者：
Leinwand, LA
中科院分区：
文献类型：
--
作者：
Lucas, DT;Aryal, P;Leinwand, LA
家族性肥厚型心肌病（HCM）是一种常染色体显性遗传疾病，其特征是不同程度的心室肥厚和肌原纤维紊乱。心肌收缩蛋白的突变会导致 HCM。然而，临床表型存在无法解释的广泛变异性，并且可能有多种影响因素。由于线粒体功能障碍已在心脏病中得到描述，因此我们测试了线粒体功能障碍导致不同 HCM 表型的假设。在两种 HCM 转基因模型中评估线粒体功能：具有突变肌球蛋白重链基因 (MyHC) 或具有突变心肌肌钙蛋白 T (R92Q) 基因的小鼠。尽管两种模型均存在线粒体超微结构异常，但仅突变型 MyHC 小鼠的状态 3 呼吸速率显着降低约 23%。值得注意的是，状态 3 呼吸的这种减少先于血流动力学功能障碍。与分离的对照线粒体相比，在分离的破坏的线粒体中测定的α-酮戊二酸脱氢酶的最大活性降低了28%。此外，突变型 MyHC 转基因小鼠中复合物 I 和 IV 减少。抑制突变型 MyHC 小鼠心脏中升高的 β-肾上腺素受体激酶，可以预防突变型 MyHC 小鼠的线粒体呼吸损伤。因此，我们的结果表明，线粒体可能导致某些形式的 HCM 中出现的血流动力学功能障碍，并为疾病表型的某些异质性提供了一种合理的机制。
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 similar to23%. 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.