Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload-associated maladaptation
Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload-associated maladaptation
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DOI：
10.1172/jci.insight.128336
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发表时间：
2019-08-22
期刊：
影响因子：
8
通讯作者：
Heineke, Joerg
中科院分区：
文献类型：
--
作者：
Mohammadi, Mona Malek;Abouissa, Aya;Heineke, Joerg
心脏压力过载-例如，由于主动脉狭窄-诱导不可逆的心肌功能障碍，心肌细胞肥大和间质纤维化的患者。与成年小鼠相比，新生小鼠在出生后第一周就能有效地再生损伤后的心脏。为了解释心脏再生不足是否会导致压力过载依赖性疾病的进展，我们在新生小鼠（nTAC）中建立了横断主动脉收缩方案。nTAC在非再生阶段（P7）诱导心功能障碍、心肌纤维化和心肌细胞肥大。相比之下，再生阶段（P1）的nTAC在很大程度上阻止了这些适应不良反应，特别是与心肌血管生成增强和心肌细胞增殖增加有关，这两者都支持nTAC期间的适应。再生和非再生nTAC后心脏的转录组学比较分析表明，转录因子GATA4是再生基因程序的主要调控因子。事实上，心肌细胞特异性的GATA4缺失将再生的nTAC转化为非再生的、适应性不良的反应。我们的新nTAC模型可用于识别压力过载期间的适应介质，并发现潜在的治疗策略。
Cardiac pressure overload - for example, due to aortic stenosis - induces irreversible myocardial dysfunction, cardiomyocyte hypertrophy, and interstitial fibrosis in patients. In contrast with adult mice, neonatal mice can efficiently regenerate the heart after injury in the first week after birth. To decipher whether insufficient cardiac regeneration contributes to the progression of pressure overload-dependent disease, we established a transverse aortic constriction protocol in neonatal mice (nTAC). nTAC in the nonregenerative stage (at P7) induced cardiac dysfunction, myocardial fibrosis, and cardiomyocyte hypertrophy. In contrast, nTAC in the regenerative stage (at P1) largely prevented these maladaptive responses and was, in particular, associated with enhanced myocardial angiogenesis and increased cardiomyocyte proliferation, which both supported adaptation during nTAC. A comparative transcriptomic analysis between hearts after regenerative versus nonregenerative nTAC suggested the transcription factor GATA4 as master regulator of the regenerative gene program. Indeed, cardiomyocyte-specific deletion of GATA4 converted the regenerative nTAC into a nonregenerative, maladaptive response. Our new nTAC model can be used to identify mediators of adaptation during pressure overload and to discover potential therapeutic strategies.