Increased serum cathepsin S in patients with atherosclerosis and diabetes

Liu, Jian; Ma, Likun; Yang, Jianwu; An, Ruihua; Sun, Zimin; Yan, Gengxing; Sun, Jiusong; Fu, Huanxian; Xu, Wei‐Hua; Hu, Chengcheng; Shi, Guo Ping

doi:10.1016/j.atherosclerosis.2005.08.001

Cited by 107 publications

(87 citation statements)

References 45 publications

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“…19 As a new finding, the results of our experiments identify a previously unknown biologic function of Cat-S (i.e., its agonistic activity of PAR2 on the surface of endothelial cells). Cat-S-mediated PAR2 activation induces ED in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 51%

Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications

Kumar

Darisipudi

Steiger

et al. 2015

JASN

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Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia-induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68 + intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage-derived circulating PAR2 agonist and mediator of endothelial dysfunction-related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases.

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Section: Discussionmentioning

confidence: 51%

Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications

Kumar

Darisipudi

Steiger

et al. 2015

JASN

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“…CTSS is synthesized by macrophages, smooth muscle cells and endothelial cells 5) and, when released extracellularly, it exerts elastolytic and collagenolytic effects, leading to elastic lamina degradation 6,7) , plaque rupture 8) and necrotic core development 7) . Some studies have reported higher concentrations of CTSS in the plasma of patients with cardiovascular disease 9,10) . Studies of animals also indicate that CTSS increases apoptosis in atherosclerotic lesions 7) , although the exact mechanisms remain unknown.…”

Section: Ctss Mrna Quantification In the Plasmamentioning

confidence: 99%

Interrelated Cathepsin S-Lowering and LDL Subclass Profile Improvements Induced by Atorvastatin in the Plasma of Stable Angina Patients

Mirjanic-Azaric

Vekić

Zeljković

et al. 2014

JAT

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Aim:We hypothesized that, in stable angina patients, atorvastatin therapy lowers the cathepsin S (CTSS) concentrations, as assessed non-invasively according to a plasma analysis. In addition, the low-density lipoprotein (LDL) and high-density lipoprotein (HDL) size and subclasses in the plasma were analysed to establish the association between CTSS and lipoprotein metabolism and determine whether this association is atorvastatin-sensitive. Methods: A total of 43 patients with stable angina received atorvastatin therapy (20 mg/day, 10 weeks). The plasma CTSS mRNA levels, CTSS protein concentrations and CTSS activity, as well as LDL and HDL size and subclasses, were analysed before and after treatment. Results: Atorvastatin treatment did not change the plasma CTSS mRNA levels, although it lowered the plasma CTSS concentrations and activity. An increased plasma CTSS concentration and activity were found to be associated with a more atherogenic LDL subclass profile (a decreased dominant LDL size and increased percentage of small, dense LDL particles). The atorvastatin-induced CTSSlowering effect was concomitant with an improvement in the LDL subclass profile, and the changes were found to be interrelated. Concomitant, interrelated changes in the CTSS levels and LDL subclass profiles were found in the LDL phenotype B patients only (a dominant LDL diameter of ≤ 25.5 nm at the start of the study). In this subgroup, lowering of the plasma CTSS mRNA level also correlated with lowering of the proportion of small, dense LDL particles. Conclusions: Atorvastatin-induced CTSS-lowering and LDL subclass profile improvements in the plasma of LDL phenotype B patients with stable angina are concomitant and interrelated. J Atheroscler Thromb, 2014; 21:868-877.

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“…Traditional cardiovascular risk factors, including dyslipidemia, smoking, hypertension, and diabetes mellitus, have been used to assess risk in the general population, 10) but these factors do not fully explain cardiovascular risk. [11][12][13] Recent studies suggest that inflammatory biomarkers such as cathepsin S, 14) CXCL16, 15,16) soluble CD40 ligand (SCD40L9), 17,18) interleukin-10 (IL-10), 19) placental growth factor (PlGF), [20][21][22] GDF15, [23][24][25] matrix metalloproteinase 9 (MMP9), 26) monocyte chemoattractant protein-1 (MCP-1), 27) and high-sensitivity C-reactive protein (hs-CRP) [28][29][30] may play potential roles in predicting the risk of developing coronary artery disease (CAD).…”

mentioning

confidence: 99%

Multimarker Approach for the Prediction of Cardiovascular Events in Patients With Mild to Moderate Coronary Artery Lesions

Zhang

Liu

et al. 2012

Int. Heart J.

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SummaryFew studies have assessed the incremental usefulness of multimarkers as predictors of cardiovascular events in patients with mild to moderate coronary artery lesions.We examined 9 plasma inflammatory cytokines (cathepsin S, CXCL16, sopluble CD40 ligand, interleukin-10, placental growth factor, GDF15, matrix metalloproteinase 9, monocyte chemoattractant protein-1, and high-sensitivity Creactive protein) in 964 patients showing mild to moderate lesions and assessed their association with risk of cardiovascular events during 3 years of follow-up (median 17 months).In a backward Cox regression procedure, Cystatin S (hazard ratio [HR]: 1.788, 95% CI:1.233 to 2.593, P = 0.02), soluble CD40 ligand (HR: 1.255, 95% CI:1.054 to 1.494, P = 0.011), placental growth factor (HR: 1.194, 95% CI:0.976 to 1.461, P = 0.035), and GDF15 (HR: 0.725, 95% CI:0.550 to 0.956, P = 0.023) were significantly related to cardiovascular events. Compared with multimarker score (according to regression coefficients of significant biomarkers) in the lowest two quintiles, patients in the highest quintile had a higher risk of cardiovascular events after adjustment for traditional risk factors (HR: 2.77, 95% CI:1.30 to 5.87, P = 0.008). Adding the multimarker score to traditional risk factors contributed significantly to the prediction of cardiovascular events (AUC increased from 0.67 to 0.72).A multimarker approach added to the predictive information obtained from traditional risk factors in patients with mild to moderate coronary artery lesions. (Int Heart J 2012; 53: 85-90)

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Increased serum cathepsin S in patients with atherosclerosis and diabetes

Cited by 107 publications

References 45 publications

Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications

Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications

Interrelated Cathepsin S-Lowering and LDL Subclass Profile Improvements Induced by Atorvastatin in the Plasma of Stable Angina Patients

Multimarker Approach for the Prediction of Cardiovascular Events in Patients With Mild to Moderate Coronary Artery Lesions

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