Caveolin-1 expression during the progression of pulmonary hypertension
Caveolin-1 expression during the progression of pulmonary hypertension
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DOI：
10.1258/ebm.2012.011382
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发表时间：
2012-08-01
影响因子：
3.2
通讯作者：
Mathew, Rajamma
中科院分区：
文献类型：
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作者：
Huang, Jing;Wolk, John H.;Mathew, Rajamma
小窝蛋白-1在维持血管健康方面起着关键作用。在野百合碱(MCT)诱导的肺动脉高压(PH)发生之前，内皮细胞小窝蛋白-1的进行性丢失以及增殖和抗凋亡通路的激活就已经发生，而拯救内皮细胞小窝蛋白-1可以减轻肺动脉高压。最近，我们报道了血管内皮细胞小窝蛋白-1的缺失与血管平滑肌细胞(SMC)小窝蛋白-1表达的增强以及随后的新生内膜形成有关。为了检验内皮细胞小窝蛋白-1的缺失和SMC中表达增强是否是PH进展过程中的一个连续事件，我们研究了MCT术后2周和4周的大鼠。观察大鼠右室收缩压、右室肥厚、肺血管组织学改变，肺组织小窝蛋白-1、内皮细胞黏附分子-1(PECAM-1)、可溶性鸟苷环化酶α和β亚基(SGC)、血管性假血友病因子(VWF)、血管平滑肌α-肌动蛋白、增殖和抗凋亡因子(PY-STAT3和Bclxl)及基质金属蛋白酶(MMP2)的表达。移植后2周和4周，PH患者伴有内皮小窝蛋白-1的进行性丢失、PY-STAT3的激活、Bclxl表达的增加和血管重塑。PECAM-1和sGC(两个亚基)的丢失与小窝蛋白-1的丢失平行，而vWF在MCT后2周保存良好。MCT后4周，除内皮小窝蛋白-1外，29%的动脉出现vWF缺失，其中70%的动脉小窝蛋白-1在SMC中表达增强，MMP2表达和活性增强。总之，MCT诱导的内皮损伤破坏内皮细胞膜，导致内皮小窝蛋白-1的进行性丢失，并激活增殖和抗凋亡途径，导致PH。随后广泛的内皮细胞损伤导致SMC小窝蛋白-1表达增强。此外，MMP2的表达和活性也呈进行性增加。这些改变可能进一步促进细胞增殖、基质降解和细胞迁移，从而促进疾病的进展。
Caveolin-1 plays a pivotal role in maintaining vascular health. Progressive loss of endothelial caveolin-1 and activation of proliferative and anti-apoptotic pathways occur before the onset of monocrotaline (MCT)-induced pulmonary hypertension (PH), and the rescue of endothelial caveolin-1 attenuates PH. Recently, we reported endothelial caveolin-1 loss associated with enhanced expression of caveolin-1 in smooth muscle cells (SMC) with subsequent neointima formation in human PH. To examine whether the loss of endothelial caveolin-1 followed by an enhanced expression in SMC is a sequential event in the progression of PH, we studied rats at two and four weeks post-MCT. Right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary vascular histology, and the expression of caveolin-1 and endothelial membrane proteins (platelet/endothelial cell adhesion molecule-1 [PECAM-1], both alpha and beta subunits of soluble guanylate cyclase [sGC]), von Willebrand factor (vWF), smooth muscle a-actin, proliferative and anti-apoptotic factors (PY-STAT3 and Bcl-xL) and matrix metalloproteinase (MMP) 2 in the lungs were examined. PH was accompanied by a progressive loss of endothelial caveolin-1, activation of PY-STAT3, increased Bcl-xL expression and vascular remodeling at two and four weeks post-MCT. Loss of PECAM-1 and sGC (both subunits) paralleled that of caveolin-1, whereas vWF was well preserved at two weeks post-MCT. At four weeks post-MCT, 29% of the arteries showed a loss of vWF in addition to endothelial caveolin-1, and 70% of these arteries exhibited enhanced expression of caveolin-1 in SMC; and there was increased expression and activity of MMP2. In conclusion, MCT-induced endothelial injury disrupts endothelial cell membrane with a progressive loss of endothelial caveolin-1, and the activation of proliferative and antiapoptotic pathways leading to PH. Subsequent extensive endothelial cell damage results in enhanced expression of caveolin-1 in SMC. In addition, there is a progressive increase in MMP2 expression and activity. These alterations may further facilitate cell proliferation, matrix degradation and cell migration, thus contributing to the progression of the disease.