Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice
Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice
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DOI：
10.1161/circresaha.116.308643
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发表时间：
2016-06-10
影响因子：
20.1
通讯作者：
Wettschureck, Nina
中科院分区：
文献类型：
--
作者：
Kaur, Harmandeep;Takefuji, Mikito;Wettschureck, Nina
基本原理：激活的心脏成纤维细胞（CF）是心脏损伤反应的关键参与者;然而，过度的纤维化可能导致心肌硬化和心力衰竭的发展。抑制激活CF已被建议作为一种治疗策略，在心脏疾病，但这是否真正改善心脏功能是uncleared.Objective：研究CF消融对心脏remodeling.Methods和结果的影响：我们的特点亚组的小鼠CF单细胞表达分析，并确定骨膜蛋白的标记物显示最高的相关性激活CF表型。我们产生了细菌人工染色体转基因小鼠，允许他莫昔芬诱导的Cre在骨膜蛋白阳性细胞的表达，以及他们的白喉毒素介导的消融。在健康心脏中，骨膜蛋白表达仅限于瓣膜成纤维细胞;消融该人群不影响心脏功能。在慢性血管紧张素II暴露后，消融激活的CF导致心脏纤维化显著减少和心脏功能改善。心肌梗死后，消融表达骨膜蛋白的CF导致纤维化减少而不影响瘢痕稳定性，心功能显著改善。单细胞转录分析显示，CF激活减少，但增加了促肥大因子在心脏巨噬细胞和心肌细胞的表达，导致局部心肌细胞hypertrophy.Conclusions：激活CF人口的调制是一个很有前途的方法，以防止不良的心脏重塑血管紧张素II和心肌梗死后。
Rationale: Activated cardiac fibroblasts (CF) are crucial players in the cardiac damage response; excess fibrosis, however, may result in myocardial stiffening and heart failure development. Inhibition of activated CF has been suggested as a therapeutic strategy in cardiac disease, but whether this truly improves cardiac function is unclear.Objective: To study the effect of CF ablation on cardiac remodeling.Methods and Results: We characterized subgroups of murine CF by single-cell expression analysis and identified periostin as the marker showing the highest correlation to an activated CF phenotype. We generated bacterial artificial chromosome-transgenic mice allowing tamoxifen-inducible Cre expression in periostin-positive cells as well as their diphtheria toxin-mediated ablation. In the healthy heart, periostin expression was restricted to valvular fibroblasts; ablation of this population did not affect cardiac function. After chronic angiotensin II exposure, ablation of activated CF resulted in significantly reduced cardiac fibrosis and improved cardiac function. After myocardial infarction, ablation of periostin-expressing CF resulted in reduced fibrosis without compromising scar stability, and cardiac function was significantly improved. Single-cell transcriptional analysis revealed reduced CF activation but increased expression of prohypertrophic factors in cardiac macrophages and cardiomyocytes, resulting in localized cardiomyocyte hypertrophy.Conclusions: Modulation of the activated CF population is a promising approach to prevent adverse cardiac remodeling in response to angiotensin II and after myocardial infarction.