美國(guó)凱斯西儲(chǔ)大學(xué)醫(yī)學(xué)院的研究人員已確定一個(gè)防止血管形成阻塞的重要遺傳因子,，這一發(fā)現(xiàn)或?qū)?dǎo)致心血管疾病的新療法,。該研究成果發(fā)表在11月19日《臨床研究期刊》上。
研究小組發(fā)現(xiàn),，負(fù)責(zé)調(diào)節(jié)血管內(nèi)皮細(xì)胞的遺傳因子KLF4的短缺，將更易形成有害牙菌斑和脂肪沉積,。此外,，他們還發(fā)現(xiàn)，KLF4不足使血管更易形成斑塊,。斑塊積累（即動(dòng)脈粥樣硬化）使血管變窄,，為血栓形成導(dǎo)致心臟病和中風(fēng)發(fā)作打下基礎(chǔ)。相反,，足夠水平的KLF4將保護(hù)血管內(nèi)襯免遭可觸發(fā)形成斑塊和凝塊的毒素和其他有害物質(zhì)的侵害,。
研究人員表示，該研究回答了關(guān)于血管健康的一個(gè)基本問(wèn)題,，即發(fā)現(xiàn)了KLF4是內(nèi)皮細(xì)胞最主要功能的主調(diào)控器,。這些遺傳因子的水平因人體疾病而改變,，因此以此為靶標(biāo)或是可行的治療策略,。
研究人員目前正在開(kāi)發(fā)工具，以發(fā)現(xiàn)可增加KLF4水平的小分子,。從長(zhǎng)遠(yuǎn)來(lái)看，研究人員的目標(biāo)是鑒別出一類(lèi)新的分子,，并藉此研制出一種藥物,，與現(xiàn)已用于心臟疾病治療的藥物共同發(fā)揮作用。另一種可能則是對(duì)現(xiàn)有藥物進(jìn)行改進(jìn)以提高KLF4水平,。(生物谷Bioon.com)
DOI:10.1172/JCI66056
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Endothelial Kruppel-like factor 4 protects against atherothrombosis in mice
Guangjin Zhou1, Anne Hamik1, Lalitha Nayak1, Hongmei Tian1, Hong Shi1, Yuan Lu1, Nikunj Sharma1, Xudong Liao1, Andrew Hale1, Lauren Boerboom2, Ryan E. Feaver3, Huiyun Gao1, Amar Desai4, Alvin Schmaier3, Stanton L. Gerson4, Yunmei Wang1, G. Brandon Atkins1, Brett R. Blackman2,3, Daniel I. Simon1 and Mukesh K. Jain1
The endothelium regulates vascular homeostasis, and endothelial dysfunction is a proximate event in the pathogenesis of atherothrombosis. Stimulation of the endothelium with proinflammatory cytokines or exposure to hemodynamic-induced disturbed flow leads to a proadhesive and prothrombotic phenotype that promotes atherothrombosis. In contrast, exposure to arterial laminar flow induces a gene program that confers a largely antiadhesive, antithrombotic effect. The molecular basis for this differential effect on endothelial function remains poorly understood. While recent insights implicate Kruppel-like factors (KLFs) as important regulators of vascular homeostasis, the in vivo role of these factors in endothelial biology remains unproven. Here, we show that endothelial KLF4 is an essential determinant of atherogenesis and thrombosis. Using in vivo EC-specific KLF4 overexpression and knockdown murine models, we found that KLF4 induced an antiadhesive, antithrombotic state. Mechanistically, we demonstrated that KLF4 differentially regulated pertinent endothelial targets via competition for the coactivator p300. These observations provide cogent evidence implicating endothelial KLFs as essential in vivo regulators of vascular function in the adult animal.
