Identification of MMP9 as a Novel Biomarker to Mitochondrial Metabolism Disorder and Oxidative Stress in Calcific Aortic Valve Stenosis

作者全名："Liu, Cong; Liu, Ruixue; Cao, Zhezhe; Guo, Qiao; Huang, He; Liu, Liangming; Xiao, Yingbin; Duan, Chenyang; Ma, Ruiyan"

作者地址："[Liu, Cong; Cao, Zhezhe; Xiao, Yingbin; Ma, Ruiyan] Army Med Univ, Xinqiao Hosp, Dept Cardiovasc Surg, Chongqing 400037, Peoples R China; [Liu, Cong] Huazhong Univ Sci & Technol, Dept Ultrasound Med, Union Hosp, Tongji Med Coll, Wuhan 430022, Peoples R China; [Liu, Ruixue; Guo, Qiao; Huang, He; Duan, Chenyang] Chongqing Med Univ, Affiliated Hosp 2, Dept Anesthesiol, Chongqing 400010, Peoples R China; [Liu, Liangming] Army Med Univ, Daping Hosp, Dept Shock & Transfus, State Key Lab Trauma Burns & Combined Injury, Chongqing 400042, Peoples R China"

通信作者："Xiao, YB; Ma, RY (通讯作者)，Army Med Univ, Xinqiao Hosp, Dept Cardiovasc Surg, Chongqing 400037, Peoples R China.; Duan, CY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Anesthesiol, Chongqing 400010, Peoples R China."

来源：OXIDATIVE MEDICINE AND CELLULAR LONGEVITY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000892030700001

JCR分区：Q2

影响因子：7.31

年份：2022

卷号：2022

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Calcific aortic valve stenosis (CAVS) is the most common heart valve disorder among humans. To date, no effective method has been identified to prevent this disease. Herein, we aimed to identify novel diagnostic and mitochondria-related biomarkers of CAVS, based on two machine learning algorithms. We further explored their association with infiltrating immune cells and studied their potential function in CAVS. The GSE12644, GSE51472, and GSE83453 expression profiles were downloaded from the Gene Expression Omnibus (GEO) repository. The GSE12644 and GSE51472 datasets were integrated to identify differentially expressed genes (DEGs). GSE12644 contains 10 normal and 10 CAVS samples, whereas GSE51472 contains 5 normal and 10 CAVS samples. GO and KEGG assays of DEGs were conducted, and the correlation between matrix metalloproteinase 9 (MMP9) expression and immune cell infiltration was explored, using CIBERSORT. The LASSO regression model and SVM-RFE analysis were used to identify diagnostic genes. The expression of MMP9 in CAVS and non-CAVS samples was measured using RT-PCR, western blotting and immunohistochemistry. A series of functional experiments were performed to explore the potential role of MMP9 in mitochondrial metabolism and oxidative stress during CAVS progression. Twenty-two DEGs were identified, of which six genes (SCG2, PPBP, TREM1, CCL19, WIF1, and MMP9) were ultimately distinguished as diagnostic genes in CAVS. Of these, MMP9 was indicated as a mitochondria-related gene, the expression and diagnostic value of which were further confirmed in the GSE83453 dataset. Correlation analysis revealed a positive correlation between MMP9 and infiltrating immune cells. In our cohort, MMP9 expression was distinctly increased in CAVS samples, and its inhibition attenuated the calcification of valve interstitial cells (VICs) by suppressing mitochondrial damage and oxidative stress. Taken together, our findings suggest MMP9 as a novel mitochondrial dysfunction biomarker and therapeutic target for CAVS."

基金机构："National Natural Science Foundation of China [82270378, 82272252]; Chongqing Talents Program [cstc2022ycjh-bgzxm0007]; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University"

基金资助正文："This work was supported by the National Natural Science Foundation of China (No. 82270378 and 82272252), Chongqing Talents Program (cstc2022ycjh-bgzxm0007), and the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University. We thank Prof. Tao Li from Army Medical University for the help with experimental equipment."