A Dual Role for Death Receptor 5 in Regulating Cardiac Fibroblast Function.
A Dual Role for Death Receptor 5 in Regulating Cardiac Fibroblast Function.
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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。
DOI：
10.3389/fcvm.2021.699102
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发表时间：
2021
影响因子：
3.6
通讯作者：
Grisanti LA
中科院分区：
文献类型：
--
作者：
Tanner MA;Grisanti LA
纤维化反应几乎涉及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明确。我们之前的研究确定了DR5在心脏成纤维细胞中的表达，然而，DR5对成纤维细胞功能的影响仍未被探索。为了研究DR5在心脏成纤维细胞中的作用，在内源性配体TRAIL或小分子激动剂bioymifi治疗后，研究了成纤维细胞的各种功能。DR5激活不诱导naïve成纤维细胞凋亡，但激活ERK1/2信号增加增殖。然而，在激活并分化成肌成纤维细胞后，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DR5调控对体内成纤维细胞的影响，采用慢性异丙肾上腺素给药心衰模型。与接受异丙肾上腺素治疗的动物相比，野生型（WT）小鼠肥大、心肌细胞死亡和纤维化增加，收缩力下降。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，与异丙肾上腺素处理的WT动物相比，观察到心肌细胞死亡和肥大增加。与WT相比，异丙肾上腺素治疗的DR5KO小鼠有增强的纤维化反应，这与收缩性的额外降低相对应。这些发现确定了DR5在心脏成纤维细胞功能中的双重作用，通过增强naïve成纤维细胞增殖，在分化为肌成纤维细胞时转换为促凋亡功能。这在心衰中是很重要的，因为DR5的激活抑制了不适应的重塑，可能是治疗心衰的一个新的治疗靶点。
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.
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影响因子：
5.6
作者：
Fang L;Murphy AJ;Dart AM
通讯作者：
Dart AM
影响因子：
5.3
作者：
Finnberg, N;Gruber, JJ;El-Deiry, WS
通讯作者：
El-Deiry, WS
影响因子：
5.6
作者：
Fredj, S;Bescond, J;Potreau, D
通讯作者：
Potreau, D
DOI：
10.1536/jhj.44.833
发表时间：
2003-11-01
期刊：
JAPANESE HEART JOURNAL
影响因子：
--
作者：
Nakajima, H;Yanase, N;Mizuguchi, J
通讯作者：
Mizuguchi, J
影响因子：
--
作者：
Bernardi S;Bossi F;Toffoli B;Fabris B
通讯作者：
Fabris B