Nature Medicine:Notch信號通路與肺動脈高血壓形成

Notch是一種在肺動脈高血壓中發揮作用的普通信號分子，如今科學家發現，這種作用是因抵達肺部的氧氣不足所造成的，新成果發表在日前在線出版的《自然—醫學》期刊上。新研究強調了Notch在肺動脈高血壓形成過程中的重要性，Notch也將成為這種疾病幹涉性治療的新靶標。

平滑肌形成了肺動脈中的膜，Notch信號分子不僅控制了平滑肌的增生，而且在未分化的狀態中維持了平滑肌細胞。肺動脈高血壓的特徵之一是小肺動脈中平滑肌細胞的過度增生，導致肺部血壓的升高，並最終導致心力衰竭和死亡。

Patricia Thistlethwaite和同事的研究顯示，人類肺動脈高血壓的特徵之一是肺部小動脈平滑肌中NOTCH3基因的過度表達。她們還發現，無論是小鼠還是人類，這種疾病的嚴重程度與肺部中的NOTCH3蛋白質濃度有關。

在缺少氧氣的情況下，缺失NOTCH3的小鼠也不會發生肺動脈高血壓。而且，通過控制和阻斷平滑肌細胞中NOTCH3的活性，可以治療普通小鼠的肺動脈高血壓。最後，科學家們發現，NOTCH3調控信號促使平滑肌更加傾向於不分化的增生狀態。（生物谷Bioon.com）

Notch Signaling Pathway：

Notch信號傳導途徑在無脊椎動物和脊椎動物中廣泛存在且高度保守。此途徑介導由局部細胞間相互作用而產生的、對多種不成熟細胞分化的抑制信號, 在胚胎發育中起重要作用。哺乳類動物中Notch途徑的功能複雜多樣, 參與造血、T細胞發育、血管生成等重要生理過程，並與腫瘤形成和某些神經系統疾病有密切關係。

Notch pathway elements

來源：José Luis de la Pompa Lab

Cell Stem Cell：Notch信號調節乳腺幹細胞

PNAS：NOTCH基因變異與肺癌發病有關

Neuron：神經祖細胞Notch信號調節

Nature：Notch信號通道研究

Nature Medicine：Notch蛋白對形成骨和力量起關鍵作用

生物谷推薦原始出處：

Nature Medicine 15, 1289 - 1297 (2009) 25 October 2009 | doi:10.1038/nm.2021

Notch3 signaling promotes the development of pulmonary arterial hypertension

Xiaodong Li1, Xiaoxue Zhang1, Robin Leathers1, Ayako Makino2, Chengqun Huang1, Pouria Parsa1, Jesus Macias3, Jason X-J Yuan2, Stuart W Jamieson1 & Patricia A Thistlethwaite1

Notch receptor signaling is implicated in controlling smooth muscle cell proliferation and in maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension is characterized by excessive vascular resistance, smooth muscle cell proliferation in small pulmonary arteries, leading to elevation of pulmonary vascular resistance, right ventricular failure and death. Here we show that human pulmonary hypertension is characterized by overexpression of NOTCH3 in small pulmonary artery smooth muscle cells and that the severity of disease in humans and rodents correlates with the amount of NOTCH3 protein in the lung. We further show that mice with homozygous deletion of Notch3 do not develop pulmonary hypertension in response to hypoxic stimulation and that pulmonary hypertension can be successfully treated in mice by administration of N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a -secretase inhibitor that blocks activation of Notch3 in smooth muscle cells. We show a mechanistic link from NOTCH3 receptor signaling through the Hairy and enhancer of Split-5 (HES-5) protein to smooth muscle cell proliferation and a shift to an undifferentiated smooth muscle cell phenotype. These results suggest that the NOTCH3–HES-5 signaling pathway is crucial for the development of pulmonary arterial hypertension and provide a target pathway for therapeutic intervention.

1 Division of Cardiothoracic Surgery, University of California–San Diego (UCSD), La Jolla, California, USA.
2 Division of Pulmonary and Critical Care Medicine, University of California–San Diego (UCSD), La Jolla, California, USA.
3 Department of Pathology, University of California–San Diego (UCSD), La Jolla, California, USA.