脂钙蛋白-2在肺动脉高压中的作用研究
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摘要
因异常的肺动脉平滑肌细胞增生、迁移以及对凋亡的抵抗引起的小肺动脉重构是肺动脉高压的重要病理特征。然而,正常的肺动脉平滑肌细胞增生与凋亡之间的平衡如何被破坏,如何转变为高增生倾向并抵抗凋亡,其中的细胞和分子机制仍不明确。最近在恶性疾病中的研究表明,由不同原因导致的内质网应激可能是促使细胞恶性转化的共同因素。联系到各种类型的肺动脉高压均存在不同程度的内质网应激,后者可能在肺动脉平滑肌细胞的增生性转化中发挥重要作用。脂钙蛋白-2(Lipocalin2, Lcn2),又被称为中性粒细胞明胶酶相关的Lipocalin (NGAL),近来发现其在很多良恶性疾病中对细胞的生存发挥重要作用。Lcn2可促进细胞摄取铁,而铁可促进细胞氧化应激；Lcn2可促进细胞迁移和侵袭,并促进细胞恶性转化；针对不同类型的细胞,Lcn2具有促进或抑制凋亡的作用。Lcn2的这些功能作用均与肺动脉高压时发生的病理变化密切相关,而目前尚未见Lcn2与肺动脉高压相关的研究报道,这促使我们对Lcn2在肺动脉高压中的可能作用展开研究。本研究主要考察了Lcn2对肺动脉平滑肌细胞凋亡、增生、迁移的影响,以及相关的分子机理；考察了在野百合碱诱导的大鼠肺动脉高压模型中Lcn2以及相关蛋白的表达变化；还检测了先天性心脏病相关的肺动脉高压患者的血浆Lcn2水平,以及与疾病临床特征的相关性。结果表明,Lcn2通过上调SOD的表达可降低细胞ROS水平,进而可抑制多种因素诱导的肺动脉平滑肌细胞凋亡；Lcn2通过促进细胞摄取铁引起轻度内质网应激,进而可促进细胞增生；Lcn2还可促进肺动脉平滑肌细胞迁移。在野百合碱诱导的大鼠肺动脉高压模型中,Lcn2的表达显著上调；与不伴肺动脉高压的单纯先天性心脏病患者相比,先天性心脏病相关的肺动脉高压患者的血浆Lcn2水平显著上调,而且血浆Lcn2水平与肺动脉压力存在较强的统计学相关性。研究结果提示,Lcn2可能在肺动脉高压的发生以及进展中发挥重要作用。
A key feature of pulmonary arterial hypertension (PH) is the remodeling of small pulmonary arteries, which is due to abnormal pulmonary artery smooth muscle cell (PASMC) proliferation, migration and resistance to apoptosis. While the cellular mechanisms of how the normal PASMC switched to proliferative and resistant to apoptosis remains unknown. Recent studies show that endoplasmic reticulum stress (ERS) may be the original reason in cell metastatic transvertion. Considering that ERS is a conmen feature in PH of every type, it is assumed play important roles in PH. Lipocalin2(Lcn2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is reported recently play roles in cell survival in a wide array of benign and malignant conditions. Lcn2is reported could augment cellular Iron level and the later is a known promotion factor in cell oxidative stress. Lcn2is also reported play roles in cell migration and invasion and could promote cancer metastasis. While in cell apoptosis, conflicting observations were reported about Lcn2in different cell types. All these functions of Lcn2are tightly concerned in PH, and remarkably, there is no report about roles of Lcn2in PH and in survival of PASMC until now. This elicits us to study the roles of Lcn2in PH. In this study, we investigated weather Lcn2regulate human PASMC apoptosis, proliferation and migration, and the mechanism involved. We investigated the level of Lcn2in rat PH model induced by monocrotaline. We also examined the plasma level of Lcn2in patients of congenital heart disease associated PH (CHD-PH), and investigated the association between Lcn2level and features of CHD-PH. In our results, Lcn2up-regulates the expression of superoxide dismutases (SOD1and SOD2) and lowers the cellular ROS. Lcn2greatly decreased the sensitivity of HPASMC to serum deprivation, H2O2and hypoxia. Through Ki67and BrdU examination, Lcn2was proved could promote HPASMC proliferation, which is due to slightly increased ERS via promoting HPASMC uptake iron. Lcn2could also promote HPASMC migration. The expression of Lcn2is elevated in rat PH model, and interestingly, the plasma Lcn2levels in patients with congenital heart disease associated PH was significantly higher than those with congenital heart diseases but no PH (CHD-nonPH). There is a significant correlation between Plasma Lcn2level and the key parameters of PH. Lcn2plays a key role in the pathogenesis and progression of PH.
A key feature of pulmonary arterial hypertension (PH) is the remodeling of small pulmonary arteries, which is due to abnormal pulmonary artery smooth muscle cell (PASMC) proliferation, migration and resistance to apoptosis. While the cellular mechanisms of how the normal PASMC switched to proliferative and resistant to apoptosis remains unknown. Recent studies show that endoplasmic reticulum stress (ERS) may be the original reason in cell metastatic transvertion. Considering that ERS is a conmen feature in PH of every type, it is assumed play important roles in PH. Lipocalin2(Lcn2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is reported recently play roles in cell survival in a wide array of benign and malignant conditions. Lcn2is reported could augment cellular Iron level and the later is a known promotion factor in cell oxidative stress. Lcn2is also reported play roles in cell migration and invasion and could promote cancer metastasis. While in cell apoptosis, conflicting observations were reported about Lcn2in different cell types. All these functions of Lcn2are tightly concerned in PH, and remarkably, there is no report about roles of Lcn2in PH and in survival of PASMC until now. This elicits us to study the roles of Lcn2in PH. In this study, we investigated weather Lcn2regulate human PASMC apoptosis, proliferation and migration, and the mechanism involved. We investigated the level of Lcn2in rat PH model induced by monocrotaline. We also examined the plasma level of Lcn2in patients of congenital heart disease associated PH (CHD-PH), and investigated the association between Lcn2level and features of CHD-PH. In our results, Lcn2up-regulates the expression of superoxide dismutases (SOD1and SOD2) and lowers the cellular ROS. Lcn2greatly decreased the sensitivity of HPASMC to serum deprivation, H2O2and hypoxia. Through Ki67and BrdU examination, Lcn2was proved could promote HPASMC proliferation, which is due to slightly increased ERS via promoting HPASMC uptake iron. Lcn2could also promote HPASMC migration. The expression of Lcn2is elevated in rat PH model, and interestingly, the plasma Lcn2levels in patients with congenital heart disease associated PH was significantly higher than those with congenital heart diseases but no PH (CHD-nonPH). There is a significant correlation between Plasma Lcn2level and the key parameters of PH. Lcn2plays a key role in the pathogenesis and progression of PH.
引文
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