Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction.
Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction.
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DOI：
10.1161/circresaha.109.216101
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发表时间：
2010-08-06
影响因子：
20.1
通讯作者：
Frangogiannis NG
中科院分区：
文献类型：
--
作者：
Dobaczewski M;Bujak M;Li N;Gonzalez-Quesada C;Mendoza LH;Wang XF;Frangogiannis NG
心肌成纤维细胞是心肌纤维化发病过程中的关键效应细胞。转化生长因子(TGF)-βSmad3信号在梗死愈合的边界区被激活，并诱导梗死心室的纤维化重塑，促进舒张功能障碍的发展。我们的研究通过剖析Smad3在调节心脏成纤维细胞表型和功能中的作用，探讨了Smad3的成纤维作用机制。Smad3缺失小鼠和相应的野生型（WT）对照进行再灌注心肌梗死方案。令人惊讶的是，Smad3−/−梗死灶中胶原沉积减少与肌成纤维细胞浸润增加有关。体外研究表明，TGF-β1抑制小鼠心脏成纤维细胞增殖；这些抗增殖作用是通过Smad3介导的。Smad3−/−成纤维细胞功能缺陷，与野生型细胞相比，胶原晶格收缩受损。收缩功能下降与TGF-β-诱导的α-平滑肌肌动蛋白表达减弱有关。此外，Smad3−/−成纤维细胞在血清刺激下迁移活性降低，TGF-β诱导的细胞外基质蛋白合成上调减弱。结缔组织生长因子（CTGF）是TGF-β诱导纤维化的重要下游介质，其上调部分依赖于Smad3。CTGF刺激以不依赖smad3的方式增强心肌成纤维细胞细胞外基质蛋白的表达。Smad3的破坏导致大量功能低下的成纤维细胞浸润梗死区，表现出肌成纤维细胞转分化受损、迁移潜力降低和纤维化相关基因表达抑制。
Cardiac fibroblasts are key effector cells in the pathogenesis of cardiac fibrosis. Transforming Growth Factor (TGF)-βSmad3 signaling is activated in the border zone of healing infarcts and induces fibrotic remodeling of the infarcted ventricle contributing to the development of diastolic dysfunction. Our study explores the mechanisms responsible for the fibrogenic effects of Smad3 by dissecting its role in modulating cardiac fibroblast phenotype and function. Smad3 null mice and corresponding wildtype (WT) controls underwent reperfused myocardial infarction protocols. Surprisingly, reduced collagen deposition in Smad3 −/− infarcts was associated with increased infiltration with myofibroblasts. In vitro studies demonstrated that TGF-β1 inhibited murine cardiac fibroblast proliferation; these anti-proliferative effects were mediated via Smad3. Smad3 −/− fibroblasts were functionally defective, exhibiting impaired collagen lattice contraction when compared to wildtype cells. Decreased contractile function was associated with attenuated TGF-β-induced expression of α-smooth muscle actin. In addition, Smad3 −/− fibroblasts had decreased migratory activity upon stimulation with serum, and exhibited attenuated TGF-β-induced upregulation of extracellular matrix protein synthesis. Upregulation of connective tissue growth factor (CTGF), an essential downstream mediator in TGF-β-induced fibrosis, was in part dependent on Smad3. CTGF stimulation enhanced extracellular matrix protein expression by cardiac fibroblasts in a Smad3-independent manner. Disruption of Smad3 results in infiltration of the infarct with abundant, hypofunctional fibroblasts that exhibit impaired myofibroblast transdifferentiation, reduced migratory potential, and suppressed expression of fibrosis-associated genes.