Endoplasmic reticulum stress-activated nuclear factor-kappa B signaling pathway induces the upregulation of cardiomyocyte dopamine D1 receptor in heart failure
Endoplasmic reticulum stress-activated nuclear factor-kappa B signaling pathway induces the upregulation of cardiomyocyte dopamine D1 receptor in heart failure
复制标题
内质网应激激活核因子-κB信号通路诱导心力衰竭心肌细胞多巴胺D1受体上调
DOI：
10.1016/j.bbrc.2022.11.031
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发表时间：
2022
影响因子：
3.1
通讯作者：
Issei Komuro
中科院分区：
文献类型：
--
作者：
Shun Nakamura;Genri Numata;Toshihiro Yamaguchi;Hiroyuki Tokiwa;Yasutomi Higashikuni;Seitaro Nomura;Tetsuo Sasano;Eiki Takimoto;Issei Komuro
多巴胺D1受体（D1R）由drd1基因编码，在心力衰竭的心肌细胞中被诱导，引发心力衰竭相关的室性心律失常，因此可能是慢性心力衰竭的潜在治疗靶点。然而，对D1R表达的调控尚不完全清楚。在这里，我们探索了在衰竭心脏中诱导心肌细胞D1R的分子机制。我们使用转录因子亲和预测（TRAP）方法对drd1基因的启动子区域进行了基序分析，并确定了核因子κB （NF-κB）作为调节drd1基因表达的候选转录因子。接下来，我们采用了由横断主动脉收缩（TAC）引起的慢性压力过载心力衰竭的小鼠模型，并评估了心肌drd1表达水平和NF-κB活性，以及内质网（ER）应激，这与心力衰竭的发病机制有关。drd1在TAC心脏中的诱导依赖于心力衰竭的严重程度，并与NF-κB激活和内质网应激相关，分别通过p65磷酸化和内质网应激相关基因的表达来评估。我们进一步通过NF-κB激活培养的新生大鼠心室肌细胞，检测内质网应激对ifdrd1的诱导作用。Tunicamycin以内质网应激依赖的方式激活NF-κB通路，增加drd1的表达。重要的是，通过Bay11-7082预处理抑制NF-κB通路完全抑制了tunicamycin诱导的drd1上调，这表明NF-κB的激活对这种调节至关重要。我们的研究表明内质网应激诱导的NF-κB活化在心肌细胞D1R的诱导中起关键作用。干预这一途径可能是治疗心力衰竭相关室性心律失常的一种新的治疗策略。
Dopamine D1 receptor (D1R), coded by theDrd1gene, is induced in cardiomyocytes of failing hearts, triggering heart failure-associated ventricular arrhythmia, and therefore could be a potential therapeutic target for chronic heart failure. The regulation of D1R expression, however, is not fully understood. Here, we explored the molecular mechanism by which cardiomyocyte D1R is induced in failing hearts. We performed motif analysis for the promoter region of theDrd1gene using the transcription factor affinity prediction (TRAP) method and identified nuclear factor-kappa B (NF-κB) as a candidate transcriptional factor regulating the expression of theDrd1gene. We next employed murine models of heart failure from chronic pressure overload by transverse aortic constriction (TAC), and assessed myocardialDrd1expression levels and NF-κB activity, as well as endoplasmic reticulum (ER) stress, which has been implicated in the pathogenesis of heart failure.Drd1induction in TAC hearts was dependent on the severity of heart failure, and was associated with NF-κB activation and ER stress,as assessed by p65 phosphorylation and the expression of ER stress-related genes, respectively. We further tested ifDrd1was induced by ER stress via NF-κB activation in cultured neonatal rat ventricular myocytes. Tunicamycin activated NF-κB pathway in an ER stress-dependent manner and increasedDrd1expression. Importantly, inhibition of NF-κB pathway by pretreatment with Bay11-7082 completely suppressed the tunicamycin-induced upregulation ofDrd1, suggesting that NF-κB activation is essential to this regulation. Our study demonstrates the pivotal role for the ER stress-induced NF-κB activation in the induction of D1R in cardiomyocytes. Intervention of this pathway might be a potential new therapeutic strategy for heart failure-associated ventricular arrhythmia.