The role of neutrophil elastase in aortic valve calcification

作者全名:"Liu, Yan; Jiang, Peng; An, Liqin; Zhu, Mengying; Li, Jin; Wang, Yue; Huang, Qin; Xiang, Yi; Li, Xiaorong; Shi, Qiong; Weng, Yaguang"

作者地址:"[Liu, Yan; Jiang, Peng; An, Liqin; Zhu, Mengying; Li, Jin; Wang, Yue; Huang, Qin; Xiang, Yi; Li, Xiaorong; Shi, Qiong; Weng, Yaguang] Chongqing Med Univ, Dept Lab Med, MOE Key Lab Lab Med Diagnost, Chongqiong, Peoples R China"

通信作者:"Shi, Q; Weng, YG (通讯作者),Chongqing Med Univ, Dept Lab Med, MOE Key Lab Lab Med Diagnost, Chongqiong, Peoples R China."

来源:JOURNAL OF TRANSLATIONAL MEDICINE

ESI学科分类:CLINICAL MEDICINE

WOS号:WOS:000781359900001

JCR分区:Q1

影响因子:7.4

年份:2022

卷号:20

期号:1

开始页: 

结束页: 

文献类型:Article

关键词:Calcific aortic valve diease; Neutrophil elastase; Valve interstitial cells; Osteogenic differentiation; Inflammation

摘要:"Background Calcific aortic valve disease (CAVD) is the most commonly valvular disease in the western countries initiated by inflammation and abnormal calcium deposition. Currently, there is no clinical drug for CAVD. Neutrophil elastase (NE) plays a causal role in inflammation and participates actively in cardiovascular diseases. However, the effect of NE on valve calcification remains unclear. So we next explore whether it is involved in valve calcification and the molecular mechanisms involved. Methods NE expression and activity in calcific aortic valve stenosis (CAVD) patients (n = 58) and healthy patients (n = 30) were measured by enzyme-linked immunosorbent assay (ELISA), western blot and immunohistochemistry (IHC). Porcine aortic valve interstitial cells (pVICs) were isolated and used in vitro expriments. The effects of NE on pVICs inflammation, apoptosis and calcification were detected by TUNEL assay, MTT assay, reverse transcription polymerase chain reaction (RT-PCR) and western blot. The effects of NE knockdown and NE activity inhibitor Alvelestat on pVICs inflammation, apoptosis and calcification under osteogenic medium induction were also detected by RT-PCR, western blot, alkaline phosphatase staining and alizarin red staining. Changes of Intracellular signaling pathways after NE treatment were measured by western blot. Apolipoprotein E-/(-) (APOE(-)/(-)) mice were employed in this study to establish the important role of Alvelestat in valve calcification. HE was used to detected the thickness of valve. IHC was used to detected the NE and alpha-SMA expression in APOE(-)/(-) mice. Echocardiography was employed to assess the heat function of APOE(-)/(-) mice. Results The level and activity of NE were evaluated in patients with CAVD and calcified valve tissues. NE promoted inflammation, apoptosis and phenotype transition in pVICs in the presence or absence of osteogenic medium. Under osteogenic medium induction, NE silencing or NE inhibitor Alvelestat both suppressed the osteogenic differentiation of pVICs. Mechanically, NE played its role in promoting osteogenic differentiation of pVICs by activating the NF-kappa B and AKT signaling pathway. Alvelestat alleviated valve thickening and decreased the expression of NE and alpha-SMA in western diet-induced APOE(-)/(-) mice. Alvelestat also reduced NE activity and partially improved the heart function of APOE(-)/(-)mice. Conclusions Collectively, NE is highly involved in the pathogenesis of valve calcification. Targeting NE such as Alvelestat may be a potential treatment for CAVD."

基金机构:National Natural Science Foundation of China [81672103]

基金资助正文:This work was supported by the National Natural Science Foundation of China (Grant No. 81672103).