Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload
Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload
复制标题
DOI：
10.1172/jci40295
复制
发表时间：
2010-01-01
影响因子：
15.9
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Takeda, Norifumi;Manabe, Ichiro;Nagai, Ryozo
成纤维细胞是心脏中数量最多的细胞类型，在体外与心肌细胞相互作用并影响其功能;然而，它们被认为在心脏肥大和衰竭中起次要作用。在这里，我们已经表明，心脏成纤维细胞是必不可少的保护和肥大的心肌反应，在体内的压力超负荷小鼠。单倍不足的转录因子编码基因Kruppel样因子5（Klf 5）抑制心脏纤维化和肥大引起的中等强度的压力超负荷，而心肌细胞特异性Klf 5缺失没有改变肥大反应。相比之下，心脏成纤维细胞特异性Klf 5缺失改善了心脏肥大和纤维化，表明成纤维细胞中的KLF 5对于压力超负荷的反应是重要的，并且心脏成纤维细胞是心肌细胞肥大所必需的。高强度压力超负荷导致Klf 5缺失成纤维细胞小鼠严重心力衰竭和早期死亡。KLF 5反式激活心脏成纤维细胞中的Igf 1，IGF-1随后以旁分泌方式诱导心肌细胞的肥大反应。IGF 1诱导对于心脏保护反应是必不可少的，因为IGF-1的肽抑制剂的施用严重加剧了由高强度压力超负荷诱导的心力衰竭。因此，心脏成纤维细胞在心肌对压力超负荷的适应性反应中起着关键作用，这种作用部分由KLF 5控制。心脏成纤维细胞功能的调节可能为治疗心力衰竭提供一种新的策略，KLF 5是一个有吸引力的靶点。
Fibroblasts, which are the most numerous cell type in the heart, interact with cardiomyocytes in vitro and affect their function; however, they are considered to play a secondary role in cardiac hypertrophy and failure. Here we have shown that cardiac fibroblasts are essential for the protective and hypertrophic myocardial responses to pressure overload in vivo in mice. Haploinsufficiency of the transcription factor-encoding gene Kruppel-like factor 5 (Klf5) suppressed cardiac fibrosis and hypertrophy elicited by moderate-intensity pressure overload, whereas cardiomyocyte-specific Klf5 deletion did not alter the hypertrophic responses. By contrast, cardiac fibroblast-specific Klf5 deletion ameliorated cardiac hypertrophy and fibrosis, indicating that KLF5 in fibroblasts is important for the response to pressure overload and that cardiac fibroblasts are required for cardiomyocyte hypertrophy. High-intensity pressure overload caused severe heart failure and early death in mice with Klf5-null fibroblasts. KLF5 transactivated Igf1 in cardiac fibroblasts, and IGF-1 subsequently acted in a paracrine fashion to induce hypertrophic responses in cardiomyocytes. Igf1 induction was essential for cardioprotective responses, as administration of a peptide inhibitor of IGF-1 severely exacerbated heart failure induced by high-intensity pressure overload. Thus, cardiac fibroblasts play a pivotal role in the myocardial adaptive response to pressure overload, and this role is partly controlled by KLF5. Modulation of cardiac fibroblast function may provide a novel strategy for treating heart failure, with KLF5 serving as an attractive target.