The Role Of Lipocalin-2in Pulmonary Hypertension

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.