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NPR3 protects cardiomyocytes from apoptosis through inhibition of cytosolic BRCA1 and TNF-alpha

机译：NPR3通过抑制胞浆BRCA1和TNF-α保护心肌细胞免于凋亡

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摘要

Natriuretic peptide receptor 3 (NPR3) is a clearance receptor by binding and internalizing natriuretic peptides (NPs) for ultimate degradation. Patients with cardiac failure show elevated NPs. NPs are linked to poor long-term survival because of their apoptotic effects. However, the underling mechanisms have not been identified yet. Here we report the role of NPR3 in anti-apoptosis via the breast cancer type 1 susceptibility protein (BRCA1) and tumor necrosis factor (TNF- ). To demonstrate a role for NPR3 in apoptosis, stable H9C2 cardiomyocyte cell lines using shRNA to knockdown NPR3 were generated. The activities of caspase-3, 8, and 9 were significantly increased in NPR3 knockdown H9C2 cardiomyocytes. Knockdown of NPR3 increased the expression of BRCA1. Also NPR3 knockdown remarkably increased the activity of cAMP response element-binding protein (CREB), a positive regulatory element for BRCA1 expression. BRCA1 showed dispersed nuclear localization in non-cardiomyocytes while predominantly cytoplasmic localization in H9C2 cells. Meanwhile, NPR3 knockdown significantly increased TNF- gene expression. These data show that NPR3 knockdown in H9C2 cells triggered both extrinsic and intrinsic apoptotic pathways. NPR3 protects cardiomyocytes from apoptosis through inhibition of cytosolic BRCA1 and TNF-, which are regulators of apoptosis. Our studies demonstrate anti-apoptosis role of NPR3 in protecting cardiomyocytes and establish the first molecular link between NP system and programmed cell death.
机译：利钠肽受体3（NPR3）是通过结合和内化利钠肽（NP）最终降解的清除受体。心力衰竭患者的NPs升高。 NP由于其凋亡作用而与较差的长期存活有关。但是，尚未确定基础机制。在这里，我们报告NPR3通过1型乳腺癌敏感性蛋白（BRCA1）和肿瘤坏死因子（TNF-）在抗凋亡中的作用。为了证明NPR3在凋亡中的作用，产生了使用shRNA敲低NPR3的稳定H9C2心肌细胞系。在NPR3基因敲低的H9C2心肌细胞中，caspase-3、8和9的活性显着增加。击倒NPR3增加BRCA1的表达。 NPR3敲低也显着提高了cAMP反应元件结合蛋白（CREB）的活性，这是BRCA1表达的阳性调控元件。 BRCA1在非心肌细胞中显示分散的核定位，而在H9C2细胞中主要显示胞质定位。同时，NPR3敲低显着增加了TNF基因的表达。这些数据表明，H9C2细胞中的NPR3敲低触发了外在和内在的凋亡途径。 NPR3通过抑制细胞凋亡的BRCA1和TNF-来保护心肌细胞免于凋亡。我们的研究表明NPR3在保护心肌细胞方面具有抗凋亡作用，并在NP系统和程序性细胞死亡之间建立了第一个分子联系。

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