PMID- 34064140 OWN - NLM STAT- MEDLINE DCOM- 20210616 LR - 20210616 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 22 IP - 11 DP - 2021 May 21 TI - MMP-9 Deletion Attenuates Arteriovenous Fistula Neointima through Reduced Perioperative Vascular Inflammation. LID - 10.3390/ijms22115448 [doi] LID - 5448 AB - Matrix metalloproteinase 9 (MMP-9) expression is upregulated in vascular inflammation and participates in vascular remodeling, including aneurysm dilatation and arterial neointima development. Neointima at the arteriovenous (AV) fistula anastomosis site primarily causes AV fistula stenosis and failure; however, the effects of MMP-9 on perioperative AV fistula remodeling remain unknown. Therefore, we created AV fistulas (end-to-side anastomosis) in wild-type (WT) and MMP-9 knockout mice with chronic kidney disease to further clarify this. Neointima progressively developed in the AV fistula venous segment of WT mice during the four-week postoperative course, and MMP-9 knockout increased the lumen area and attenuated neointima size by reducing smooth muscle cell and collagen components. Early perioperative AV fistula mRNA sequencing data revealed that inflammation-related gene sets were negatively enriched in AV fistula of MMP-9 knockout mice compared to that in WT mice. qPCR results also showed that inflammatory genes, including tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), were downregulated. In addition, Western blot results showed that MMP-9 knockout reduced CD44 and RAC-alpha serine/threonine-protein kinase (Akt) and extracellular signal-regulated kinases (ERK) phosphorylation. In vitro, MMP-9 addition enhanced IL-6 and MCP-1 expression in vascular smooth muscle cells, as well as cell migration, which was reversed by an MMP-9 inhibitor. In conclusion, MMP-9 knockout attenuated AV fistula stenosis by reducing perioperative vascular inflammation. FAU - Shih, Yu-Chung AU - Shih YC AD - Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan. AD - Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. AD - Institute of Clinical Medicine, National Yang Ming University, Taipei 11221, Taiwan. AD - Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan. FAU - Chen, Po-Yuan AU - Chen PY AUID- ORCID: 0000-0003-0936-4102 AD - Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan. AD - Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan. AD - Institute of Information Science, Academia Sinica, Taipei 115, Taiwan. FAU - Ko, Tai-Ming AU - Ko TM AD - Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan. AD - Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan. AD - Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan. AD - Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. AD - Center of Intelligent Drug System and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan. FAU - Huang, Po-Hsun AU - Huang PH AD - Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. AD - Institute of Clinical Medicine, National Yang Ming University, Taipei 11221, Taiwan. AD - Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan. FAU - Ma, Hsu AU - Ma H AD - Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan. AD - Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan. AD - Department of Surgery, School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan. FAU - Tarng, Der-Cherng AU - Tarng DC AD - Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. AD - Institute of Clinical Medicine, National Yang Ming University, Taipei 11221, Taiwan. AD - Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan. AD - Institute of Physiology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. LA - eng GR - MOST-108-2314-B-075-054/Ministry of Science and Technology, Taiwan/ GR - V109C-185/Taipei Veterans General Hospital/ PT - Journal Article DEP - 20210521 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Animals MH - Arteriovenous Fistula/*genetics MH - Cell Movement/genetics MH - Inflammation/*genetics MH - Male MH - Matrix Metalloproteinase 9/*genetics MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Muscle, Smooth, Vascular/pathology MH - Myocytes, Smooth Muscle/pathology MH - Neointima/*genetics MH - Perioperative Period MH - Vascular Remodeling/genetics PMC - PMC8196691 OTO - NOTNLM OT - arteriovenous fistula OT - matrix metalloproteinase 9 OT - neointima OT - vascular inflammation COIS- The authors declare no conflict of interest. EDAT- 2021/06/03 06:00 MHDA- 2021/06/17 06:00 PMCR- 2021/05/21 CRDT- 2021/06/02 01:08 PHST- 2021/04/28 00:00 [received] PHST- 2021/05/15 00:00 [revised] PHST- 2021/05/18 00:00 [accepted] PHST- 2021/06/02 01:08 [entrez] PHST- 2021/06/03 06:00 [pubmed] PHST- 2021/06/17 06:00 [medline] PHST- 2021/05/21 00:00 [pmc-release] AID - ijms22115448 [pii] AID - ijms-22-05448 [pii] AID - 10.3390/ijms22115448 [doi] PST - epublish SO - Int J Mol Sci. 2021 May 21;22(11):5448. doi: 10.3390/ijms22115448.