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New paradigm for therapy for pulmonary hypertension

肺动脉高压治疗的新范例

基本信息

批准号：
18591726
负责人：
UEZONO Shoichi
金额：
$ 2.43万
依托单位：
Jikei University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Hypertensive pulmonary vascular disease is characterized by abnormal proliferation of vascular endothelial and smooth muscle cells, leading to pulmonary arterial hypertension (PAH), and death. Early growth response 1 (Egr-1) is a transcription factor that is rapidly activated after vascular injury, which plays an important role in vascular remodeling. We studied whether Egr-1 is a therapeutic target for PAH. o achieve effective suppression of Egr-1 in vivo, transfection with synthetic double-stranded Egr-1 decoy oligodeonucleotides was utilized in this study. Four-week-old Sprague-Dawley rats were evaluated for the development of PAH following monocrotaline (MCT, 60mg/kg) injection. Four hours prior to and just before MCT administration, either Egr-1 decoy or scrambled decoy was transfected using the hemagglutinating virus of Japan envelope vector system. Transfection of Egr-1 decoy but not scrambled decoy markedly attenuated MCT-induced PAH (mPAP=35±1 vs. 56±2, P<0.05) and vascular remodeling (VOS=0.39± 0.06 vs. 1.19±0.05, P<0.05). Egr-1 decoy may represent an effective strategy in the treatment of PAH, which provide the functional importance of Egr-1 in the MCT-induced PAH. We also investigated whether KLF 5, other transcription factor which is believed to play a pivotal role in vascular remodeling, has any impact on pulmonary vascular remodeling. Unfortunately, Am 80, a drug to suppress KLF 5 activity failed to reduce PA pressure in MCT induced PH in rats. We concluded KLF5 may not be a therapeutic target for PAH.

高血压性肺血管疾病的特征是血管内皮细胞和平滑肌细胞的异常增殖，导致肺动脉高压（PAH）和死亡。早期生长反应1（Earlygrowthrespons 1，Egr-1）是血管损伤后迅速激活的一种转录因子，在血管重塑中起重要作用。我们研究了Egr-1是否是PAH的治疗靶点。为了在体内实现Egr-1的有效抑制，在本研究中使用了用合成的双链Egr-1诱饵寡核苷酸转染。评价4周龄Sprague-Dawley大鼠注射野百合碱（MCT，60 mg/kg）后PAH的发展。在MCT给药前4小时和即将给药前，使用日本包膜载体系统的血凝病毒转染Egr-1诱饵或乱序诱饵。转染Egr-1诱骗基因（而非乱序诱骗基因）可显著减轻MCT诱导的PAH（mPAP=35±1 vs.56 ±2，P<0.05）和血管重构（VOS=0.39± 0.06 vs.1.19 ±0.05，P<0.05）。Egr-1诱饵可能代表了治疗PAH的有效策略，这提供了Egr-1在MCT诱导的PAH中的功能重要性。我们还研究了其他被认为在血管重建中起关键作用的转录因子KLF 5是否对肺血管重建有任何影响。在MCT诱导的大鼠肺动脉高压模型中，抑制KLF 5活性的Am 80不能降低PA压力。我们得出结论，KLF 5可能不是PAH的治疗靶点。