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Alteration of tissue inhibitors of matrix metalloproteinases (TIMP)/matrix metalloproteinases (MMP) associated with collagen upregulation has an important role in sustained atrial fibrillation (AF). The expression of miR‐146b‐5p, whose the targeted gene is TIMPs, is upregulated in atrial cardiomyocytes during AF. This study was to determine whether miR‐146b‐5p could regulate the gene expression of TIMP4 and the contribution of miRNA to atrial fibrosis in AF. Collagen synthesis was observed after miR‐146b‐5p transfection in human induced pluripotent stem cell‐derived atrial cardiomyocytes (hiPSC‐aCMs)‐fibroblast co‐culture cellular model in vitro. Furthermore, a myocardial infarction (MI) mouse model was used to confirm the protective effect of miR‐146b‐5p downregulation on atrial fibrosis. The expression level of miR‐146b‐5p was upregulated, while the expression level of TIMP4 was downregulated in the fibrotic atrium of canine with AF. miR‐146b‐5p transfection in hiPSC‐aCMs‐fibroblast co‐culture cellular model increased collagen synthesis by regulating TIMP4/MMP9 mediated extracellular matrix proteins synthesis. The inhibition of miR‐146b‐5p expression reduced the phenotypes of cardiac fibrosis in the MI mouse model. Fibrotic marker MMP9, TGFB1 and COL1A1 were significantly downregulated, while TIMP4 was significantly upregulated (at both mRNA and protein levels) by miR‐146b‐5p inhibition in cardiomyocytes of MI heart. We concluded that collagen fibres were accumulated in extracellular space on miR‐146b‐5p overexpressed co‐culture cellular model. Moreover, the cardiac fibrosis induced by MI was attenuated in antagomiR‐146 treated mice by increasing the expression of TIMP4, which indicated that the inhibition of miR‐146b‐5p might become an effective therapeutic approach for preventing atrial fibrosis.

The abnormal expression of tissue inhibitor of metalloproteinase 4 (TIMP4) is associated with multiple human cancers. However, the role of TIMP4 in oral squamous cell carcinoma (OSCC) remains elusive. Therefore, this study explored the expression profile and prognosis of TIMP4 in OSCC. Tumor and adjacent non-tumor tissues were collected from OSCC patients, and protein expression of TIMP4 was detected through immunohistochemistry (IHC) and positive cell counting. Additionally, The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma (TCGA-HNSCC) dataset was used to analyze TIMP4 expression further to determine its relationship with HNSCC clinical characteristics. Kaplan-Meier analysis was used to evaluate survival and prognosis. Meanwhile, the Tumor Immune Estimation Resource (TIMER) database was employed to assess the correlation between TIMP4 expression and tumor immune infiltration. Computational tools were also applied to investigate the involvement of TIMP4 in cancer pathways. Results showed that TIMP4 was decreased in OSCC and HNSCC compared with normal tissues. The decrease in TIMP4 was associated with cancer metastasis, immune suppression and HPV positive, clinical staging. Overall, these findings demonstrate that TIMP4 is significantly reduced in OSCC and HNSCC, and associated with a poor prognosis. Additional investigations are warranted to fully understand the therapeutic potential of TIMP4 in OSCC.

To investigate the involvement of transforming growth factor-β1 (TGF-β1) and tissue inhibitor of metalloproteinase 4 (TIMP-4) in influencing the severity of atrial fibrosis in rheumatic heart disease (RHD) patients with atrial fibrillation (AF). The degree of myocardial fibrosis was evaluated using Masson staining. The expression levels of TGF-β1, TIMP-4, matrix metalloproteinase-2 (MMP-2), type I collagen, and type III collagen were estimated by Western blot analysis. Additionally, TGF-β1 and TIMP-4 mRNA levels were quantified by qRT-PCR. The effect of TGF-β1 stimulation on TIMP-4 expression was assessed by in vitro stimulation of freshly isolated human atrial fibroblasts with recombinant human TGF-β1, followed by Western blot analysis to detect changes in TIMP-4 levels. Masson stain revealed that the left atrial diameter and collagen volume fraction were obviously increased in AF patients, compared to sinus rhythm (SR) controls (both P  < 0.05). Western blot analysis showed significantly elevated levels of the AF markers MMP-2, type I collagen, and type III collagen in the AF group, in comparison to the SR controls (all P  < 0.05). In the AF group, TGF-β1 expression was relatively higher, while TIMP-4 expression was apparently lower than the SR group (all P  < 0.05). TIMP-4 expression level showed a negative association with TGF-β1 expression level ( r  = −0.98, P  < 0.01) and TGF-β1 stimulation of atrial fibroblasts led to a sharp decrease in TIMP-4 protein level. Increased TGF-β1 expression and decreased TIMP-4 expression correlated with atrial fibrosis and ECM changes in the atria of RHD patients with AF. Notably, TGF-β1 suppressed TIMP-4 expression, suggesting that selective TGF-β1 inhibitors may be useful therapeutic agents.

Background Despite several therapies, pulmonary hypertension (PH) is still a severe disease which can lead to right heart failure. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in cardiac and vascular remodeling in PH. Therefore, these biomarkers play an important role in PH patients. This study investigated whether TIMP-4, MMP-2, and N-terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) plasma levels are useful in assessing the severity of PH and other clinical or echocardiographic parameters. Methods The concentrations of MMP-2, TIMP-4, and NT-proBNP in 68 PH patients were compared with those of 12 controls without PH. All patients underwent a physical examination, echocardiography, and were checked for the presence of cardiovascular risk factors; also, plasma concentrations of MMP-2, TIMP-4, NT-proBNP, total cholesterol, and triglycerides were determined. Results In PH patients, significantly elevated plasma levels of TIMP-4 (PH: 2877.99 ± 1363.78 pg/ml, control: 2028.38 ± 762.67 pg/ml, p  = 0.0068) and NT-proBNP ( PH: 2405.00 pg/ml—5423.47 ± 6703.38 pg/ml, control: 411.0000 pg/ml—421.75 ± 315.37 pg/ml, p  = 0.01) were detected. We also observed that MMP-2 and NT-proBNP were significantly increased in patients with higher WHO functional class ( p  = 0.001 for MMP-2, p  = 0.008 for NT-proBNP), higher pressure in the pulmonary artery ( p  = 0.002 for MMP-2, p  = 0.001 for NT-proBNP), and more severe tricuspid regurgitation ( p  = 0.001 for MMP-2, p  = 0.009 for NT-proBNP). TIMP-4 was elevated in patients with more severe pressure in the pulmonary artery ( p  = 0.006). Conclusions The plasma levels of TIMP-4 and NT-proBNP are higher in PH patients. MMP-2 and NT-proBNP correlates with different PH parameters severity (WHO functional class, sPAP severity, TV regurgitation severity). Therefore, plasmatic levels of MMP-2 and NT-proBNP at this kind of patients reflect disease severity and may have a prognostic role. MMP-2 can help assess the beneficial effects of PH pharmacotherapy on tissue remodeling. These remodeling biomarkers may not have a diagnostic value but they have the potential to predict survival. Nevertheless, a greater understanding of the involvement of MMPs in PH is mandatory to further explore the prognostic role and the possibilities of therapeutic MMP inhibition in PH.

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) are potential regulators of tuberculosis (TB) pathology. Whether they are candidates for non-sputum-based biomarkers for pulmonary TB (PTB) and extra-pulmonary TB (EPTB) is not fully understood. Hence, to examine the association of MMPs and TIMPs with PTB and EPTB, we have measured the circulating levels of MMPs (MMP-1, 2, 3, 7, 8, 9, 12, and 13) and TIMPs (TIMP-1, 2, 3, and 4) in PTB, EPTB and compared them with latent tuberculosis (LTB) or healthy control (HC) individuals. We have also assessed their circulating levels before and after the completion of anti-tuberculosis treatment (ATT). Our data describes that systemic levels of MMP-1, 8, 9, 12 were significantly increased in PTB compared to EPTB, LTB, and HC individuals. In contrast, MMP-7 was significantly reduced in PTB compared to EPTB individuals. Likewise, the systemic levels of MMP-1, 7, 13 were significantly increased in EPTB in comparison to LTB and HC individuals. In contrast, MMP-8 was significantly reduced in EPTB individuals compared to LTB and HC individuals. In addition, the systemic levels of TIMP-1, 2, 3 were significantly diminished and TIMP-4 levels were significantly enhanced in PTB compared to EPTB, LTB, and HC individuals. The circulating levels of TIMP-2 was significantly reduced and TIMP-3 was significantly elevated in EPTB individuals in comparison with LTB and HCs. Some of the MMPs (7, 8, 9, 12, 13 in PTB and 1, 7, 8, 9 in EPTB) and TIMPs (1, 2, 3, 4 in PTB and 4 in EPTB) were significantly modulated upon treatment completion. ROC analysis showed that MMP-1, 9 and TIMP-2, 4 could clearly discriminate PTB from EPTB, LTB and HCs and MMP-13 and TIMP-2 could clearly discriminate EPTB from LTB and HCs. Additionally, multivariate analysis also indicated that these alterations were independent of age and sex in PTB and EPTB individuals. Therefore, our data demonstrates that MMPs and TIMPs are potential candidates for non-sputum-based biomarkers for differentiating PTB and EPTB from LTB and HC individuals.

There has been limited research on assessing metalloproteinases (MMPs) 1, 2, and 7, as well as their tissue inhibitors (TIMPs) 1, 2, 3, and 4 in the context of polytrauma. These proteins play crucial roles in various physiological and pathological processes and could be a reliable tool in polytrauma care. We aimed to determine their clinical relevance. We assessed 24 blunt polytrauma survivors and 12 fatalities (mean age, 44.2 years, mean ISS, 45) who were directly admitted to our Level I trauma center and spent at least one night in the intensive care unit. We measured serum levels of the selected proteins on admission (day 0) and days 1, 3, 5, 7, and 10. The serum levels of the seven proteins varied considerably among individuals, resulting in similar median trend curves for TIMP1 and TIMP4 and for MMP1, MMP2, TIMP2, and TIMP3. We also found a significant interrelationship between the MMP2, TIMP2, and TIMP3 levels at the same measurement points. Furthermore, we calculated significant cross-correlations between MMP7 and MMP1, TIMP1 and MMP7, TIMP3 and MMP1, TIMP3 and MMP2, and TIMP4 and TIMP3 and an almost significant correlation between MMP7 and TIMP1 for a two-day-lag. The autocorrelation coefficient reached statistical significance for MMP1 and TIMP3. Finally, lower TIMP1 serum levels were associated with in-hospital mortality upon admission. The causal effects and interrelationships between selected proteins might provide new insights into the interactions of MMPs and TIMPs. Identifying the underlying causes might help develop personalized therapies for patients with multiple injuries. Administering recombinant TIMP1 or increasing endogenous production could improve outcomes for those with multiple injuries. However, before justifying further investigations into basic research and clinical relevance, our findings must be validated in a multicenter study using independent cohorts to account for clinical and biological variability.

Background Tissue inhibitors of metalloproteinase (TIMP) family proteins are peptidases involved in extracellular matrix (ECM) degradation. Various diseases are related to TIMPs, and the primary reason is that TIMPs can indirectly regulate remodelling of the ECM and cell signalling by regulating matrix metalloproteinase (MMP) activity. However, the link between TIMPs and glioblastoma (GBM) is unclear. Objective This study aimed to explore the role of TIMP expression and immune infiltration in GBM. Methods Oncomine, GEPIA, OSgbm, LinkedOmics, STRING, GeneMANIA, Enrichr, and TIMER were used to conduct differential expression, prognosis, and immune infiltration analyses of TIMPs in GBM. Results All members of the TIMP family had significantly higher expression levels in GBM. High TIMP3 expression correlated with better overall survival (OS) and disease-specific survival (DSS) in GBM patients. TIMP4 was associated with a long OS in GBM patients. We found a positive relationship between TIMP3 and TIMP4, identifying gene sets with similar or opposite expression directions to those in GBM patients. TIMPs and associated genes are mainly associated with extracellular matrix organization and involve proteoglycan pathways in cancer. The expression levels of TIMPs in GBM correlate with the infiltration of various immune cells, including CD4+ T cells, macrophages, neutrophils, B cells, CD8 + T cells, and dendritic cells. Conclusions Our study inspires new ideas for the role of TIMPs in GBM and provides new directions for multiple treatment modalities, including immunotherapy, in GBM.

Matrix metalloproteinases (MMPs) are involved in remodeling of the extracellular matrix (ECM) during pregnancy and parturition. Aberrant ECM degradation by MMPs or an imbalance between MMPs and their tissue inhibitors (TIMPs) have been implicated in the pathogenesis of preterm labor, however few studies have investigated MMPs or TIMPs in maternal serum. Therefore, the purpose of this study was to determine serum concentrations of MMP-3, MMP-9 and all four TIMPs as well as MMP:TIMP ratios during term and preterm labor. A case control study with 166 singleton pregnancies, divided into four groups: (1) women with preterm birth, delivering before 34 weeks (PTB); (2) gestational age (GA) matched controls, not in preterm labor; (3) women at term in labor and (4) at term not in labor. MMP and TIMP concentrations were measured using Luminex technology. MMP-9 and TIMP-4 concentrations were higher in women with PTB vs. GA matched controls (resp. p = 0.01 and p<0.001). An increase in MMP-9:TIMP-1 and MMP-9:TIMP-2 ratio was observed in women with PTB compared to GA matched controls (resp. p = 0.02 and p<0.001) as well as compared to women at term in labor (resp. p = 0.006 and p<0.001). Multiple regression results with groups recoded as three key covariates showed significantly higher MMP-9 concentrations, higher MMP-9:TIMP-1 and MMP-9:TIMP-2 ratios and lower TIMP-1 and -2 concentrations for preterm labor. Significantly higher MMP-9 and TIMP-4 concentrations and MMP-9:TIMP-2 ratios were observed for labor. Serum MMP-9:TIMP-1 and MMP-9:TIMP-2 balances are tilting in favor of gelatinolysis during preterm labor. TIMP-1 and -2 concentrations were lower in preterm gestation, irrespective of labor, while TIMP-4 concentrations were raised in labor. These observations suggest that aberrant serum expression of MMP:TIMP ratios and TIMPs reflect pregnancy and labor status, providing a far less invasive method to determine enzymes essential in ECM remodeling during pregnancy and parturition.

To establish appropriate ex vivo models for a glaucomatous trabecular meshwork (TM), two-dimensional (2D) and three-dimensional (3D) cultures of human trabecular meshwork cells (HTM) were prepared in the presence of 250 nM dexamethasone (DEX) or 5 ng/mL TGFβ2, and characterized by the following analyses; transendothelial electrical resistance (TEER) measurements, FITC dextran permeability, scanning electron microscopy and the expression of the extracellular matrix (ECM) including collagen (COL)1, 4 and 6, and fibronectin (FN), α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase (TIMP)1–4, and matrix metalloproteinase (MMP)2, 9 and 14. DEX and TGFβ2 both caused a significant increase or decrease in the TEER values and FITC dextran permeability. During the 3D spheroid culture, DEX or TGFβ2 induced a mild and significant down-sizing and an increase in stiffness, respectively. TGFβ2 induced a significant up-regulation of COL1 and 4, FN, α-SMA, and MMP 2 and 14 (2D) or COL1 and 6, and TIMP2 and 3 (3D), and DEX induced a significant up-regulation of FN (3D) and TIMP4 (2D and 3D). The findings presented herein indicate that DEX or TGFβ2 resulted in mild and severe down-sized and stiff 3D HTM spheroids, respectively, thus making them viable in vitro HTM models for steroid-induced and primary open angle glaucoma.

Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, resulting in inconsistent findings across studies. Identifying a core set of genes consistently involved in COPD pathogenesis, independent of patient variability, is essential. Methods We integrated lung tissue sequencing data from patients with COPD across two centers. We used weighted gene co-expression network analysis and machine learning to identify 13 potential pathogenic genes common to both centers. Additionally, a gene-based model was constructed to distinguish COPD at the molecular level and validated in independent cohorts. Gene expression in specific cell types was analyzed, and Mendelian randomization was used to confirm associations between candidate genes and lung function/COPD. Preliminary in vitro functional validation was performed on prioritized core candidate genes. Results Tissue inhibitor of metalloproteinase 4 (TIMP4) was identified as a key pathogenic gene and validated in COPD cohorts. Further analysis using single-cell sequencing from mice and patients with COPD revealed that TIMP4 is involved in ciliated cells. In primary human airway epithelial cells cultured at the air-liquid interface, TIMP4 overexpression reduced ciliated cell numbers. Conclusions We developed a 13-gene model for distinguishing COPD at the molecular level and identified TIMP4 as a potential hub pathogenic gene. This finding provides insights into shared disease mechanisms and positions TIMP4 as a promising therapeutic target for further investigation.