Increased Postnatal Cardiac Hyperplasia Precedes Cardiomyocyte Hypertrophy in a Model of Hypertrophic Cardiomyopathy.
Increased Postnatal Cardiac Hyperplasia Precedes Cardiomyocyte Hypertrophy in a Model of Hypertrophic Cardiomyopathy.
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DOI：
10.3389/fphys.2017.00414
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发表时间：
2017
影响因子：
4
通讯作者：
Ralphe JC
中科院分区：
文献类型：
--
作者：
Farrell ET;Grimes AC;de Lange WJ;Armstrong AE;Ralphe JC
原理：肥厚性心肌病（HCM）发生在约0.5%的人群中，是年轻人心源性猝死（SCD）的主要原因。心肌细胞肥大已被公认为HCM心脏增大的机制，但对引起肥大的早期信号转导机制知之甚少。心肌肌球蛋白结合蛋白C（MYBPC 3）的突变是最常见的HCM引起的突变之一。HCM小鼠模型（cMyBP-C−/−）中Mybpc 3的消融在出生后第9天（PND）迅速导致心脏肥大，尽管心脏在出生时与野生型（WT）无法区分。这个模型提供了一个独特的机会，探讨早期过程中所涉及的戏剧性的产后过渡到肥大。方法和结果：我们进行了微阵列分析、超声心动图、qPCR、免疫组织化学（IHC）和分离的心肌细胞测量，以表征明显肥大前后围产期cMyBP-C−/−表型。cMyBP-C−/−心脏在PND 1时显示细胞周期升高，到PND 9时转变为肥大。扩展的时间过程表明，心肌细胞周期的增加与细胞肥大之前心脏重量与体重比的升高有关，这表明细胞周期导致心肌细胞增殖。cMyBP-C缺失杂合的动物倾向于纯合无效的方向，但在PND 9时未显示心脏大小增加。结论：结果表明，在cMyBP-C−/− HCM模型中，细胞周期途径调节的改变和增殖的升高先于肥大，并表明心肌细胞数量的增加有助于cMyBP-C−/−小鼠心脏大小的增加。这个肥大前期可能反映了一个独特的时间，在此期间，HCM的承诺是确定的，疾病的严重程度受到影响。
Rationale: Hypertrophic cardiomyopathy (HCM) occurs in ~0.5% of the population and is a leading cause of sudden cardiac death (SCD) in young adults. Cardiomyocyte hypertrophy has been the accepted mechanism for cardiac enlargement in HCM, but the early signaling responsible for initiating hypertrophy is poorly understood. Mutations in cardiac myosin binding protein C (MYBPC3) are among the most common HCM-causing mutations. Ablation of Mybpc3 in an HCM mouse model (cMyBP-C−/−) rapidly leads to cardiomegaly by postnatal day (PND) 9, though hearts are indistinguishable from wild-type (WT) at birth. This model provides a unique opportunity to explore early processes involved in the dramatic postnatal transition to hypertrophy. Methods and Results: We performed microarray analysis, echocardiography, qPCR, immunohistochemistry (IHC), and isolated cardiomyocyte measurements to characterize the perinatal cMyBP-C−/− phenotype before and after overt hypertrophy. cMyBP-C−/− hearts showed elevated cell cycling at PND1 that transitioned to hypertrophy by PND9. An expanded time course revealed that increased cardiomyocyte cycling was associated with elevated heart weight to body weight ratios prior to cellular hypertrophy, suggesting that cell cycling resulted in cardiomyocyte proliferation. Animals heterozygous for the cMyBP-C deletion trended in the direction of the homozygous null, yet did not show increased heart size by PND9. Conclusions: Results indicate that altered regulation of the cell cycling pathway and elevated proliferation precedes hypertrophy in the cMyBP-C−/− HCM model, and suggests that increased cardiomyocyte number contributes to increased heart size in cMyBP-C−/− mice. This pre-hypertrophic period may reflect a unique time during which the commitment to HCM is determined and disease severity is influenced.