Opposing Actions of Fibroblast and Cardiomyocyte Smad3 Signaling in the Infarcted Myocardium.
Opposing Actions of Fibroblast and Cardiomyocyte Smad3 Signaling in the Infarcted Myocardium.
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DOI：
10.1161/circulationaha.117.029622
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发表时间：
2018-02-13
期刊：
影响因子：
37.8
通讯作者：
Frangogiannis NG
中科院分区：
文献类型：
--
作者：
Kong P;Shinde AV;Su Y;Russo I;Chen B;Saxena A;Conway SJ;Graff JM;Frangogiannis NG
转化生长因子-βS通过激活SmAD依赖和SmAD不依赖的级联反应来调节广泛的细胞反应。在梗塞的心脏中，Smad3信号在心肌细胞和间质细胞中都被激活。我们假设Smad3的细胞特异性作用调节梗死心肌的修复和重塑。为了剖析细胞特异性的Smad3在心肌梗死中的作用，我们建立了Smad3在活化的成纤维细胞或心肌细胞中缺失的小鼠。用超声心动图评估再灌流或非再灌流后的心功能。通过组织学研究、蛋白质和基因表达水平的评估，研究了细胞特异性Smad3缺失对心肌梗死的影响。在体外，我们研究了Smad依赖和Smad非依赖的心脏成纤维细胞的作用。成纤维细胞特异性Smad3缺失的小鼠在再灌流后加重了不利的重构，并在非再灌流后表现出更高的晚期破裂发生率。成纤维细胞特异性Smad3缺失的后果不是由于急性脑梗塞面积的影响，而是与成纤维细胞不受抑制的增殖、受损的瘢痕重塑、成纤维细胞来源的胶原合成减少以及梗死区肌成纤维细胞排列紊乱有关。天狼星红染色切片的偏光显微镜显示，成纤维细胞形态的变化与梗死区胶原基质的组织紊乱有关。相反，心肌梗死成纤维细胞α-SMA的表达不受Smad3缺失的影响。Smad3关键调控成纤维细胞功能，激活整合素介导的NADPH氧化酶(NOX)-2的表达。心肌细胞中Smad3的缺失减轻了心肌梗死后的重构和功能障碍。心肌细胞特异性Smad3缺失不影响急性心肌梗死范围，但与重塑心肌中心肌细胞凋亡减少有关，伴随着心肌NOX2水平降低，亚硝化应激减少，以及基质金属蛋白酶-2表达降低。在治疗心肌梗死中，肌成纤维细胞和心肌细胞特异性激活的Smad3具有不同的功能结果，可能涉及整合素/活性氧轴的激活。
Transforming Growth Factor (TGF)-βs regulate a wide range of cellular responses by activating Smad-dependent and Smad-independent cascades. In the infarcted heart, Smad3 signaling is activated in both cardiomyocytes and interstitial cells. We hypothesized that cell-specific actions of Smad3 regulate repair and remodeling in the infarcted myocardium. In order to dissect cell-specific Smad3 actions in myocardial infarction, we generated mice with Smad3 loss in activated fibroblasts, or in cardiomyocytes. Cardiac function was assessed following reperfused or non-reperfused infarction using echocardiography. The effects of cell-specific Smad3 loss on the infarcted heart were studied using histological studies, assessment of protein and gene expression levels. In vitro, we studied Smad-dependent and Smad-independent actions in isolated cardiac fibroblasts. Mice with fibroblast-specific Smad3 loss had accentuated adverse remodeling following reperfused infarction, and exhibited an increased incidence of late rupture following non-reperfused infarction. The consequences of fibroblast-specific Smad3 loss were not due to effects on acute infarct size, but were associated with unrestrained fibroblast proliferation, impaired scar remodeling, reduced fibroblast-derived collagen synthesis, and perturbed alignment of myofibroblast arrays in the infarct. Polarized light microscopy in sirius red-stained sections demonstrated that the changes in fibroblast morphology were associated with perturbed organization of the collagenous matrix in the infarcted area. In contrast, α-SMA expression by infarct myofibroblasts was not affected by Smad3 loss. Smad3 critically regulated fibroblast function, activating integrin-mediated NADPH oxidase (NOX)-2 expression. Smad3 loss in cardiomyocytes attenuated post-infarction remodeling and dysfunction. Cardiomyocyte-specific Smad3 loss did not affect acute infarct size, but was associated with attenuated cardiomyocyte apoptosis in the remodeling myocardium, accompanied by decreased myocardial NOX2 levels, reduced nitrosative stress, and lower matrix metalloproteinase-2 expression. In healing myocardial infarction, myofibroblast- and cardiomyocyte-specific activation of Smad3 has contrasting functional outcomes that may involve activation of an integrin/reactive oxygen axis.