Mice deficient in galectin-1 exhibit attenuated physiological responses to chronic hypoxia-induced pulmonary hypertension
Mice deficient in galectin-1 exhibit attenuated physiological responses to chronic hypoxia-induced pulmonary hypertension
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DOI：
10.1152/ajplung.00192.2006
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发表时间：
2007-01-01
影响因子：
4.9
通讯作者：
Majka, S.
中科院分区：
文献类型：
--
作者：
Case, D.;Irwin, D.;Majka, S.
肺动脉高压（PH）的特征是持续的血管收缩，随后细胞外基质（ECM）的产生和平滑肌细胞（SMC）的增殖。ECM的变化可以调节血管反应性和SMC收缩。半乳糖凝集素-1（Gal-I）是由血管、间质、上皮和免疫细胞产生的缺氧诱导的β-半乳糖苷结合凝集素。Gal-1通过与ECM的相互作用以及免疫系统功能调节SMC分化、增殖和凋亡，因此，我们研究了Gal-1在缺氧PH过程中的作用，通过定量1）Gal-1在体外和体内对缺氧的反应和2）Gal-1在缺氧PH过程中的作用。1基因缺失对PH对体内慢性缺氧反应的幅度的影响。通过构建和筛选消减文库，我们发现急性缺氧增加了肺间充质细胞中Gal-1 mRNA的表达。在野生型（WT）小鼠，Gal-1免疫反应性增加后6周的缺氧。通过定量Western分析证实Gal-1蛋白表达增加。Gal-1敲除（Gal-1（-/-））小鼠显示PH反应降低，通过右心室压力和右心室与左心室+隔膜湿重的比值测量，与WT小鼠相比。然而，WT和Gal-1（-/-）小鼠中肌化血管的数量和程度增加相似。在对慢性缺氧的反应中，两组中因子8阳性微血管密度的降低相似。WT和Gal-1（-/-）小鼠的血管反应性在体内进行了测试，并使用暴露于急性缺氧的离体灌注肺。急性缺氧导致野生型和Gal-1（-/-）小鼠的RV压力显著增加;然而，Gal-1（-/-）小鼠的反应更大。这些结果表明，Gal-1影响缺氧引起的PH期间对缺氧的收缩反应和随后的重构，从而影响疾病进展。
Pulmonary hypertension (PH) is characterized by sustained vasoconstriction, with subsequent extracellular matrix (ECM) production and smooth muscle cell (SMC) proliferation. Changes in the ECM can modulate vasoreactivity and SMC contraction. Galectin-1 (Gal-1) is a hypoxia-inducible beta-galactoside-binding lectin produced by vascular, interstitial, epithelial, and immune cells. Gal-1 regulates SMC differentiation, proliferation, and apoptosis via interactions with the ECM, as well as immune system function, and, therefore, likely plays a role in the pathogenesis of PH. We investigated the effects of Gal-1 during hypoxic PH by quantifying 1) Gal-1 expression in response to hypoxia in vitro and in vivo and 2) the effect of Gal-1 gene deletion on the magnitude of the PH response to chronic hypoxia in vivo. By constructing and screening a subtractive library, we found that acute hypoxia increases expression of Gal-1 mRNA in isolated pulmonary mesenchymal cells. In wild-type (WT) mice, Gal-1 immunoreactivity increased after 6 wk of hypoxia. Increased expression of Gal-1 protein was confirmed by quantitative Western analysis. Gal-1 knockout (Gal-1(-/-)) mice showed a decreased PH response, as measured by right ventricular pressure and the ratio of right ventricular to left ventricular + septum wet weight compared with their WT counterparts. However, the number and degree of muscularized vessels increased similarly in WT and Gal-1(-/-) mice. In response to chronic hypoxia, the decrease in factor 8-positive microvessel density was similar in both groups. Vasoreactivity of WT and Gal-1(-/-) mice was tested in vivo and with use of isolated perfused lungs exposed to acute hypoxia. Acute hypoxia caused a significant increase in RV pressure in wild-type and Gal-1(-/-) mice; however, the response of the Gal-1(-/-) mice was greater. These results suggest that Gal-1 influences the contractile response to hypoxia and subsequent remodeling during hypoxia-induced PH, which influences disease progression.