An abnormal Ca2+ response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy
An abnormal Ca2+ response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy
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DOI：
10.1172/jci11093
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发表时间：
2000-12-01
影响因子：
15.9
通讯作者：
Seidman, JG
中科院分区：
文献类型：
--
作者：
Fatkin, D;McConnell, BK;Seidman, JG
显性阴性肌瘤蛋白基因突变导致家族性肥厚性心肌病（FHC），这是一种以左心室肥厚性心绞痛为特征的疾病，呼吸困难可导致猝死。我们在此报告了一种携带心肌肌球蛋白重链基因错译突变（α MHC403/+）的小鼠FHC模型，当使用钙调磷酸酶抑制剂或K+通道激动剂治疗时，发生了加重的肥厚，组织病理学恶化，并有早期死亡的风险。尽管有不同的药理靶点，但每种药物都能增强野生型心肌细胞舒张期Ca2+浓度；α MHC403/+肌细胞没有反应。用Ca2+通道拮抗剂预处理可消除野生型肌细胞舒张期Ca2+变化，并防止α MHC403/+小鼠的过度肥厚反应。我们得出结论，fhc引起的肌瘤蛋白基因突变引起异常的Ca2+反应，引发肥厚反应。这些数据定义了突变肌瘤前肌触发心肌细胞生长和重塑心脏通路中一个重要的Ca2+依赖步骤，提供了环境影响FHC进展的明确证据，并为这种普遍的人类疾病提供了合理的治疗方法。
Dominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (alpha MHC403/+), when treated with calcineurin inhibitors or a K+-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca2+ concentrations in wild-type cardiac myocytes; alpha MHC403/+ myocytes failed to respond. Pretreatment with a Ca2+-channel antagonist abrogated diastolic Ca2+ changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated alpha MHC403/+ mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca2+ responses that initiate a hypertrophic response. These data define an important Ca2+-dependent step in the pathway by which mutant sarcomere pro reins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.