化压力导致心力衰竭
Gabriele G Schiattarella1,2, Francisco Altamirano1, Dan Tong1
1Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|April 12, 2019
概括
没有有效的治疗方法可以治疗心力衰竭与保存的喷射分数 (HFpEF). 研究人员发现,在小鼠中抑制氧化合成酶模仿了HFpEF,揭示了一种涉及X盒结合蛋白1 (XBP1) 的途径,这对心脏功能至关重要.
科学领域:
- 心血管生物学
- 分子医学
- 病理生理学
背景情况:
- 心脏衰竭与保存的喷射分数 (HFpEF) 是一个重要的临床挑战,患病率和死亡率很高.
- 目前对HFpEF的治疗策略有限,缺乏基于证据的治疗方法.
研究的目的:
- 研究HFpEF背后的分子机制.
- 确定HFpEF的潜在治疗点.
主要方法:
- 使用高脂肪饮食和N-nitro-L-arginine甲基 (L-NAME) 诱导代谢和高血压的小鼠模型,模仿HFpEF.
- 研究了心肌中未折叠蛋白质反应因子X-box-binding protein 1 (XBP1s) 的表达和功能.
- 研究了可诱导的氧化合成酶 (iNOS) 和 IRE1α-XBP1 途径在 HFpEF 发病过程中的作用.
主要成果:
- 鼠标模型成功地回顾了人类HFpEF的关键系统和心血管特征.
- 在HFpEF小鼠模型和人类患者中观察到心肌XBP1s表达的减少.
- 增加iNOS活性和随后的IRE1αS- 化导致XBP1缺陷拼接,并导致HFpEF表型.
- 在小鼠模型中,抑制iNOS或增强XBP1s改善了HFpEF表型.
结论:
- 由iNOS驱动的IRE1α-XBP1通路的失调是导致HFpEF心肌细胞功能障碍的关键机制.
- 针对iNOS-IRE1α-XBP1通路可能为HFpEF提供一种新的治疗方法.
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