Inflammatory Cells Accelerated Carotid Artery Calcification via MMP9: Evidences From Single-Cell Analysis

Abstract

Background: Vascular calcification (VC) is an important predictor of prognosis in atherosclerosis, the phenotypic transformation of vascular smooth muscle cells (VSMCs) is thought to be a process of VC. However, the implications and potential mechanisms for VSMCs phenotypic transition remain unknown.Methods: To study the transformation of vascular smooth muscle cells (VSMCs) in the calcification early period, we analyzed single-cell sequencing data from carotid artery calcified core and paracellular tissue, based on the results of enrichment analysis and protein-protein interaction analysis. Upstream transcription factors were tracked and finally the results were validated using the MESA database.Results: We successfully identified a subpopulation of inflammatory macrophage-like VSMCs and determined that MMP9 is an important factor in the phenotypic transformation of VSMCs. We found that RELA regulates MMP9 expression and that knockdown of RELA attenuated MMP9 expression and reduced the expression of BMP2 and the macrophage marker LGALS3 in vascular smooth muscle in inflammatory states, while serum levels of MMP9 correlated significantly with the inflammatory response.Conclusion: This study reveals that the phenotypic transformation of VSMCs can be regulated by modulating MMP9, providing a new idea for the early treatment of VC.

Next-Generation and Single-Cell Sequencing Approaches to Study Atherosclerosis and Vascular Inflammation Pathophysiology: A Systematic Review

“…Ten articles ( 20 , 27 , 28 , 31 , 37 , 41 , 45 – 47 , 50 ) addressed the role of SMCs in atherosclerosis and vascular inflammation. Four of these articles ( 20 , 45 , 46 , 50 ) utilized single-cell sequencing exclusively, one ( 31 ) utilized next-generation RNA sequencing exclusively, one ( 47 ) utilized next-generation micro-RNA sequencing, and the remaining four ( 27 , 28 , 37 , 41 ) utilized a combination of these methodologies, including the use of ChIP-Seq ( 27 , 28 , 37 ), ATAC-Seq ( 28 ) and CITE-Seq ( 27 ).…”

“…Liang et al ( 45 ) undertook single-cell sequencing of carotid artery calcified cores and paracellular tissue, compared to patient matched proximal adjacent to carotid artery tissue, to investigate the phenotypic transitions of SMCs during the calcification process in humans. A total of 20 clusters were categorized from this analysis, and comparison between tissue types identified a greater proportion of T-cell and monocytes in the disease-associated tissue, whilst EC and fibroblast populations were higher in the control tissue.…”

“…Of all cell types investigated in the included articles, SMCs featured predominantly ( n = 12), with attention paid predominantly to their phenotypic switching capacity in disease states ( 20 , 27 , 28 , 31 , 37 , 41 , 45 – 47 , 50 ). Macrophages were another prevalent focus of research ( n = 7), with specific attention paid to their phenotypic heterogeneity in plaque progression and regression ( 22 , 24 , 29 , 36 , 49 , 51 ).…”

Deciphering the combination mechanisms of Gualou–Xiebai herb pair against atherosclerosis by network pharmacology and HPLC-Q-TOF-MS technology

“…The study verified that higher expression of the CCL2 gene led to a higher likelihood of developing AS ( Winter et al, 2018 ). Inflammatory cells could accelerate carotid artery calcification via modulating MMP9 and cause AS ( Liang et al, 2021 ). Modulation of the AKT activity levels in macrophages significantly affected their polarization phenotype in AS mice ( Linton et al, 2019 ).…”

Imbalance of the protease-antiprotease system against the background of chronic obstructive pulmonary disease in combination with ischemic heart disease

“…Дослідники виявили низку природних поліморфізмів промоторів генів MMП людини, що змінюють транскрипційну активність. Останні дані показали: поліморфізм генів MMП-1 і MMП-12, але не MMП-9, є або причиновими факторами пов'язаного з курінням ушкодження легенів, або перебувають у нерівноважному зв'язку з причиновим поліморфізмом [16].…”