Regulated inositol-requiring protein 1-dependent decay as a mechanism of corin RNA and protein deficiency in advanced human systolic heart failure.
Regulated inositol-requiring protein 1-dependent decay as a mechanism of corin RNA and protein deficiency in advanced human systolic heart failure.
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DOI：
10.1161/jaha.114.001104
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发表时间：
2014-12
影响因子：
5.4
通讯作者：
Dries DL
中科院分区：
文献类型：
--
作者：
Lee R;Xu B;Rame JE;Felkin LE;Barton P;Dries DL
内源性利钠肽系统的补偿作用需要将利钠肽前激素充分加工成具有生物活性的羧基末端片段。利钠肽前肽加工是由心肌细胞表达的跨膜丝氨酸蛋白酶 Corin 完成的。脑钠肽（BNP）处理在晚期心力衰竭中不充分，并且与不良后果独立相关；然而，导致 BNP 加工受损的分子机制尚不清楚。我们假设，晚期心力衰竭心肌细胞内质网应激的发展会触发肌醇需求蛋白 1 (IRE1) 依赖性 corin mRNA 衰变，这将有利于有利于利尿钠肽前肽加工受损的分子底物。从移植时患有晚期心力衰竭的患者获得的两个独立的心脏样本表明，随着心房钠尿肽 (ANP)/BNP RNA 的增加，corin RNA 减少。剪接 X-box 蛋白 1（IRE1 核糖核酸内切酶活性的标志物）的增加与 corin RNA 的减少相关。此外，与未失败的对照样本相比，约 50% 的心脏显示 Corin RNA 和蛋白质显着减少。体外实验表明，用毒胡萝卜素诱导培养的心肌细胞内质网应激可激活 IRE1 的内切核糖核酸酶活性和 corin mRNA 的时间依赖性减少。在 HL-1 细胞中，IRE1 的过度表达激活 IRE1 内切核糖核酸酶活性并导致 corin mRNA 衰减，而 IRE1-RNA 对 shRNA 的干扰在用毒胡萝卜素诱导内质网应激后减弱了 corin mRNA 的衰减。用放线菌素 D 预处理细胞以抑制转录并不会改变毒胡萝卜素诱导的 corin mRNA 下降的幅度或时间进程，这支持了以下假设：这是 IRE1 介导的 corin mRNA 降解的结果。这些数据支持这样的假设：内质网应激介导的、IRE1依赖性的靶向corin mRNA衰减是一种导致corin mRNA导致相应corin蛋白缺乏的机制，可能导致患有晚期收缩性心力衰竭的人类中利尿钠肽前激素加工受损的病理生理学。
The compensatory actions of the endogenous natriuretic peptide system require adequate processing of natriuretic peptide pro‐hormones into biologically active, carboxyl‐terminal fragments. Natriuretic peptide pro‐peptide processing is accomplished by corin, a transmembrane serine protease expressed by cardiomyocytes. Brain natriuretic peptide (BNP) processing is inadequate in advanced heart failure and is independently associated with adverse outcomes; however, the molecular mechanisms causing impaired BNP processing are not understood. We hypothesized that the development of endoplasmic reticulum stress in cardiomyocytes in advanced heart failure triggers inositol‐requiring protein 1 (IRE1)‐dependent corin mRNA decay, which would favor a molecular substrate favoring impaired natriuretic peptide pro‐peptide processing. Two independent samples of hearts obtained from patients with advanced heart failure at transplant demonstrated that corin RNA was reduced as Atrial natriuretic peptide (ANP)/BNP RNA increased. Increases in spliced X‐box protein 1, a marker for IRE1‐endoribonuclease activity, were associated with decreased corin RNA. Moreover, ≈50% of the hearts demonstrated significant reductions in corin RNA and protein as compared to the nonfailing control sample. In vitro experiments demonstrated that induction of endoplasmic reticulum stress in cultured cardiomyocytes with thapsigargin activated IRE1's endoribonuclease activity and time‐dependent reductions in corin mRNA. In HL‐1 cells, overexpression of IRE1 activated IRE1 endoribonuclease activity and caused corin mRNA decay, whereas IRE1‐RNA interference with shRNA attenuated corin mRNA decay after induction of endoplasmic reticulum stress with thapsigargin. Pre‐treatment of cells with Actinomycin D to inhibit transcription did not alter the magnitude or time course of thapsigargin‐induced corin mRNA decline, supporting the hypothesis that this was the result of IRE1‐mediated corin mRNA degradation. These data support the hypothesis that endoplasmic reticulum stress‐mediated, IRE1‐dependent targeted corin mRNA decay is a mechanism leading to corin mRNA resulting in corresponding corin protein deficiency may contribute to the pathophysiology of impaired natriuretic peptide pro‐hormone processing in humans processing in humans with advanced systolic heart failure.