BACKGROUND:Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery by promoting the development of noncontractile fibrotic areas. The mechanisms that lead to cardiac fibrosis are diverse and incompletely characterized. We explored whether the expansion of cardiac fibroblasts after MI can be regulated through a paracrine action of cardiac stromal cells.METHODS:We performed a bioinformatic secretome analysis of cardiac stromal PW1⁺ cells isolated from normal and post-MI mouse hearts to identify novel secreted proteins. Functional assays were used to screen secreted proteins that promote fibroblast proliferation. The expressions of candidates were subsequently analyzed in mouse and human hearts and plasmas. The relationship between levels of circulating protein candidates and adverse post-MI cardiac remodeling was examined in a cohort of 80 patients with a first ST-segment–elevation MI and serial cardiac magnetic resonance imaging evaluations.RESULTS:Cardiac stromal PW1⁺ cells undergo a change in paracrine behavior after MI, and the conditioned media from these cells induced a significant increase in the proliferation of fibroblasts. We identified a total of 12 candidates as secreted proteins overexpressed by cardiac PW1⁺ cells after MI. Among these factors, GDF3 (growth differentiation factor 3), a member of the TGF-β (transforming growth factor-β) family, was markedly upregulated in the ischemic hearts. Conditioned media specifically enriched with GDF3 induced fibroblast proliferation at a high level by stimulation of activin-receptor–like kinases. In line with the secretory nature of this protein, we next found that GDF3 can be detected in mice and human plasma samples, with a significant increase in the days after MI. In humans, higher GDF3 circulating levels (measured in the plasma at day 4 after MI) were significantly associated with an increased risk of adverse remodeling 6 months after MI (adjusted odds ratio, 1.76 [1.03–3.00]; P=0.037), including lower left ventricular ejection fraction and a higher proportion of akinetic segments.CONCLUSIONS:Our findings define a mechanism for the profibrotic action of cardiac stromal cells through secreted cardiokines, such as GDF3, a candidate marker of adverse fibrotic remodeling after MI.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01113268.

中文翻译：

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新型心肌因子 GDF3 可预测心肌梗死后的不良纤维化重塑

背景：心肌梗塞 (MI) 诱导修复反应，最终产生稳定的纤维化疤痕。尽管疤痕可以防止心脏破裂，但过度的促纤维化反应会促进非收缩性纤维化区域的发展，从而损害最佳恢复。导致心脏纤维化的机制多种多样且特征不完全。^{我们探讨了 MI 后心脏成纤维细胞的扩增是否可以通过心脏基质细胞的旁分泌作用进行调节。方法：我们对心脏基质 PW1 +}进行了生物信息学分泌组分析从正常和 MI 后小鼠心脏中分离的细胞，用于鉴定新的分泌蛋白。功能测定用于筛选促进成纤维细胞增殖的分泌蛋白。随后在小鼠和人类的心脏和血浆中分析了候选者的表达。在 80 名患有首次 ST 段抬高 MI 和连续心脏磁共振成像评估的患者队列中检查了候选循环蛋白水平与不良 MI 后心脏重塑之间的关系。 结果：心脏基质 PW1 + 细胞^发生变化在 MI 后的旁分泌行为中，来自这些细胞的条件培养基诱导成纤维细胞增殖显着增加。我们确定了总共 12 个候选者作为心脏 PW1 ^{+过度表达的分泌蛋白}MI 后的细胞。在这些因子中，TGF-β（转化生长因子-β）家族的成员 GDF3（生长分化因子 3）在缺血心脏中显着上调。专门富含 GDF3 的条件培养基通过刺激激活素受体样激酶，诱导高水平的成纤维细胞增殖。根据这种蛋白质的分泌性质，我们接下来发现可以在小鼠和人类血浆样本中检测到 GDF3，并且在 MI 后的几天内显着增加。在人类中，较高的 GDF3 循环水平（在 MI 后第 4 天在血浆中测量）与 MI 后 6 个月不良重塑风险增加显着相关（调整后的比值比，1.76 [1.03–3.00]；P=0.037)，包括较低的左心室射血分数和较高比例的运动不能节段。结论：我们的研究结果通过分泌的心肌因子（例如 GDF3，一种 MI 后不良纤维化重塑的候选标志物）确定了心脏基质细胞促纤维化作用的机制.注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT01113268。