Aims

One unaddressed aspect of healing after myocardial infarction (MI) is how non-myocyte cells that survived the ischemic injury, keep withstanding additional cellular damage by stress forms typically arising during the post-infarction inflammation. Here we aimed to determine if cell survival is conferred by expression of a mitochondrial protein novel to the cardiac proteome, known as steroidogenic acute regulatory protein, (StAR/STARD1). Further studies aimed to unravel the regulation and role of the non-steroidogenic cardiac StAR after MI.

Methods and results

Following permanent ligation of the left anterior descending coronary artery in mouse heart, timeline western blot analyses showed that StAR expression corresponds to the inflammatory response to MI. Following the identification of StAR in mitochondria of cardiac fibroblasts in culture, confocal microscopy immunohistochemistry (IHC) identified StAR expression in left ventricular (LV) activated interstitial fibroblasts, adventitial fibroblasts and endothelial cells. Further work with the primary fibroblasts model revealed that interleukin-1α (IL-1α) signaling via NF-κB and p38 MAPK pathways efficiently upregulates the expression of the Star gene products. At the functional level, IL-1α primed fibroblasts were protected against apoptosis when exposed to cisplatin mimicry of in vivo apoptotic stress; yet, the protective impact of IL-1α was lost upon siRNA mediated StAR downregulation. At the physiological level, StAR expression was nullified during post-MI inflammation in a mouse model with global IL-1α deficiency, concomitantly resulting in a 4-fold elevation of apoptotic fibroblasts. Serial echocardiography and IHC studies of mice examined 24 days after MI revealed aggravation of LV dysfunction, LV dilatation, anterior wall thinning and adverse tissue remodeling when compared with loxP control hearts.

Conclusions

This study calls attention to overlooked aspects of cellular responses evolved under the stress conditions associated with the default inflammatory response to MI. Our observations suggest that LV IL-1α is cardioprotective, and at least one mechanism of this action is mediated by induction of StAR expression in border zone fibroblasts, which renders them apoptosis resistant. This acquired survival feature also has long-term ramifications on the heart recovery by diminishing adverse remodeling and improving the heart function after MI.

中文翻译：

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心脏成纤维细胞的白细胞介素 1α 依赖性存活与 StAR/STARD1 表达相关，并改善心肌梗死后的心脏重塑和功能

目标

心肌梗塞 (MI) 后愈合的一个未解决的方面是在缺血性损伤中幸存下来的非心肌细胞如何保持承受通常在梗塞后炎症期间出现的压力形式引起的额外细胞损伤。在这里，我们旨在确定细胞存活是否是由心脏蛋白质组新的线粒体蛋白的表达赋予的，称为类固醇急性调节蛋白 (StAR/STARD1)。进一步的研究旨在揭示心肌梗死后非类固醇性心脏 StarAR 的调节和作用。

方法和结果

在小鼠心脏左冠状动脉前降支永久结扎后，时间线蛋白质印迹分析显示，StAR 表达对应于对 MI 的炎症反应。在培养的心脏成纤维细胞线粒体中鉴定出 StAR 后，共聚焦显微镜免疫组织化学 (IHC) 鉴定了左心室 (LV) 激活的间质成纤维细胞、外膜成纤维细胞和内皮细胞中的 StAR 表达。对原代成纤维细胞模型的进一步研究表明，通过NF-κB 和 p38 MAPK 通路的白细胞介素 1α (IL-1α) 信号传导可有效上调Star基因产物的表达。在功能水平上，当暴露于顺铂模拟物时，IL-1α 引发的成纤维细胞被保护免于凋亡。体内凋亡应激；然而，IL-1α 的保护作用在 siRNA 介导的 StarAR 下调后丧失。在生理水平上，在全身 IL-1α 缺乏的小鼠模型中，在 MI 后炎症期间，StAR 表达无效，同时导致凋亡成纤维细胞升高 4 倍。与 loxP 对照心脏相比，MI 后 24 天对小鼠进行的系列超声心动图和 IHC 研究显示 LV 功能障碍加重、LV 扩张、前壁变薄和不良组织重塑。

结论

这项研究引起了人们对在与 MI 的默认炎症反应相关的压力条件下进化的细胞反应被忽视的方面的关注。我们的观察表明 LV IL-1α 具有心脏保护作用，并且这种作用的至少一种机制是通过诱导边界区成纤维细胞中的 StAR 表达介导的，这使得它们具有细胞凋亡抗性。这种获得性生存特征还通过减少不良重塑和改善 MI 后的心脏功能对心脏恢复产生长期影响。