The fibrotic response is involved in nearly all forms of heart failure and dysregulated responses can lead to enhanced cardiac dysfunction. TNF-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor (DR) 5, are associated with multiple forms of heart failure, but their role in the heart is poorly defined. Our previous study identified DR5 expression on cardiac fibroblasts however, the impact of DR5 on fibroblast function remains unexplored. To investigate the role of DR5 in cardiac fibroblasts, a variety of fibroblast functions were examined following treatment with the endogenous ligand, TRAIL, or small molecule agonist, bioymifi. DR5 activation did not induce apoptosis in naïve fibroblasts but activated ERK1/2 signaling to increase proliferation. However, upon activation and differentiation to myofibroblasts, DR5 expression was elevated, and DR5 agonists induced caspase 3 activation resulting in myofibroblast apoptosis. To investigate the impact of DR5 regulation of fibroblasts in vivo, a chronic isoproterenol administration model of heart failure was used. Wild-type (WT) mice receiving isoproterenol had increased hypertrophy, cardiomyocyte death, and fibrosis and decreased contractility compared to vehicle treated animals. DR5 knockout (KO) mice had no overt baseline phenotype however, following isoproterenol infusion, increased cardiomyocyte death and hypertrophy in comparison to isoproterenol treated WT animals was observed. DR5KO mice had an augmented fibrotic response with isoproterenol treatment compared with WT, which corresponded with additional decreases in contractility. These findings identify a dual role for DR5 in cardiac fibroblast function through enhanced naïve fibroblast proliferation, which switches to a pro-apoptotic function upon differentiation to myofibroblasts. This is important in heart failure where DR5 activation suppresses maladaptive remodeling and may represent a novel therapeutic target for the treatment of heart failure.

中文翻译：

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死亡受体 5 在调节心脏成纤维细胞功能中的双重作用。

纤维化反应涉及几乎所有形式的心力衰竭，反应失调可导致心功能障碍加剧。TNF 相关凋亡诱导配体 (TRAIL) 及其受体死亡受体 (DR) 5 与多种形式的心力衰竭有关，但它们在心脏中的作用尚不清楚。我们之前的研究确定了 DR5 在心脏成纤维细胞上的表达，然而，DR5 对成纤维细胞功能的影响仍未得到探索。为了研究 DR5 在心脏成纤维细胞中的作用，在用内源性配体 TRAIL 或小分子激动剂 bioymifi 处理后检查了多种成纤维细胞功能。DR5 激活不会诱导幼稚成纤维细胞凋亡，但会激活 ERK1/2 信号以增加增殖。然而，在激活和分化为肌成纤维细胞后，DR5 表达升高，DR5 激动剂诱导 caspase 3 激活，导致肌成纤维细胞凋亡。为了研究体内 DR5 调节对成纤维细胞的影响，使用了心力衰竭的慢性异丙肾上腺素给药模型。与载体治疗的动物相比，接受异丙肾上腺素的野生型 (WT) 小鼠肥大、心肌细胞死亡和纤维化增加，收缩力降低。DR5 敲除 (KO) 小鼠没有明显的基线表型，然而，在异丙肾上腺素输注后，与异丙肾上腺素治疗的 WT 动物相比，观察到心肌细胞死亡和肥大增加。与 WT 相比，DR5KO 小鼠对异丙肾上腺素治疗具有增强的纤维化反应，这与收缩力的额外降低相对应。这些发现通过增强幼稚成纤维细胞增殖确定了 DR5 在心脏成纤维细胞功能中的双重作用，在分化为肌成纤维细胞后转变为促凋亡功能。这在 DR5 激活抑制适应不良重塑的心力衰竭中很重要，并且可能代表治疗心力衰竭的新治疗靶点。