Lack of the Cysteine Protease Inhibitor Cystatin C Promotes Atherosclerosis in Apolipoprotein E–Deficient Mice

Bengtsson, Eva; To, Fong; Håkansson, Katarina; Grubb, Anders; Brånén, Lena; Nilsson, Jan; Jovinge, Stefan

doi:10.1161/01.atv.0000179600.34086.7d

Cited by 98 publications

(65 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, only U-CysC, but not U-B2MG and U-NAG, was significantly associated with age-adjusted CAVI, an index of arterial stiffness, in obese patients. These observations could be attributed to the following reasons: (1) U-CysC has different kinetics from U-B2MG and U-NAG, being more closely correlated with creatinine (17,19); (2) the major site of their production differs from one another (for instance, proximal renal tubules for NAG, lymphatic tissues for B2MG, and systemic nucleated cells for CysC) (35)(36)(37); and (3) each has distinct functional properties (for instance, NAG as a glycolytic enzyme and CysC as a cysteine proteinase inhibitor). Because cysteine proteinase inhibitors are involved in atherogenesis (35)(36)(37), it would be interesting to examine the role of CysC in the pathophysiology of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Urinary Cystatin C as a Potential Risk Marker for Cardiovascular Disease and Chronic Kidney Disease in Patients with Obesity and Metabolic Syndrome

Satoh‐Asahara¹,

Suganami²,

Majima³

et al. 2011

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

SummaryBackground and Objectives Obesity and metabolic syndrome (MS) increase the risk of cardiovascular disease (CVD), chronic kidney disease (CKD), and all-cause mortality. Serum cystatin C (S-CysC), a marker of GFR, has been shown to be associated with CVD and CKD. This study was designed to elucidate the association of urinary CysC (U-CysC), a marker of renal tubular dysfunction, with CVD and CKD risk factors in patients with obesity and MS. Design, setting, participants, & measurementsThe U-CysC-creatinine ratio (UCCR) was examined in 343 Japanese obese outpatients enrolled in the multi-centered Japan Obesity and Metabolic Syndrome Study.Results UCCR was positively correlated with urine albumin-creatinine ratio (UACR) and S-CysC and negatively correlated with estimated GFR (eGFR). Among obese patients, UCCR was significantly higher in MS patients than in non-MS patients. UCCR had significant correlations with the number of components of MS and arterial stiffness, all of which are CVD predictors, similarly to UACR (P Ͻ 0.05). Interestingly, diet-and exercise-induced weight reduction for 3 months significantly decreased only UCCR among all of the renal markers examined (P Ͻ 0.01), in parallel with the decrease in BMI, HbA1c, and arterial stiffness, suggesting the beneficial effect of weight reduction on renal tubular dysfunction. ConclusionsThis study demonstrates that UCCR is significantly associated with renal dysfunction, the severity of MS, arterial stiffness, and weight change in obese patients. The data of this study suggest that UCysC could serve as a CVD and CKD risk factor in patients with obesity and MS.

show abstract

Section: Discussionmentioning

confidence: 99%

Urinary Cystatin C as a Potential Risk Marker for Cardiovascular Disease and Chronic Kidney Disease in Patients with Obesity and Metabolic Syndrome

Satoh‐Asahara¹,

Suganami²,

Majima³

et al. 2011

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…This relationship with inflammatory markers was identified in the present study (data not shown). One study suggested that cystatin had an atheroprotective effect in animal experiment (19). However, there is no pathogenetic evidence that would link cystatin C to cardiovascular mortality other than its correlation with GFR.…”

Section: Discussionmentioning

confidence: 99%

Serum Cystatin C Is Related to Pulse Wave Velocity Even in Subjects with Normal Serum Creatinine

et al. 2008

View full text Add to dashboard Cite

We hypothesized that serum cystatin C can be a more predictable marker of arterial stiffness than serum creatinine and creatinine-based glomerular filtration rate (GFR). The aim of this study is to evaluate whether serum cystatin C is related to arterial stiffness independently of serum creatinine in subjects for whom serum creatinine is normal. A total of 2,018 individuals (1,120 males, 898 females) were enrolled. Mean brachial-ankle pulse wave velocity (baPWV) was used as a marker of arterial stiffness and sex-specific analysis

show abstract

“…27 It remains controversial whether cystatin C deficiency affects atherosclerosis. 28,29 Increased cathepsin L expression and decreased cystatin C have been found in human atherosclerotic plaques and aortic aneurysms. 10,30 The differential effects of laminar and oscillatory shear stresses on cathepsin L activity reported in this study may be a critical mechanism by which AAA occurs in regions of disturbed flow.…”

Section: Discussionmentioning

confidence: 99%

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Platt

Ankeny

2006

Vascular Pharmacology

View full text Add to dashboard Cite

Objective-The cysteine proteases, cathepsins, have been implicated in vascular remodeling and atherosclerosis, processes known to be regulated by shear stress. It is not known, however, whether shear regulates cathepsins. We examined the hypothesis that shear stress regulates cathepsin activity in endothelial cells. Methods and Results-Mouse aortic endothelial cells (MAECs) exposed to atheroprotective, unidirectional laminar shear (LS) degraded significantly less BODIPY-labeled elastin and gelatin in comparison to static and proatherogenic oscillatory shear (OS). The cathepsin inhibitor E64 also reduced this activity. Gelatin zymography showed that cathepsin activity of MAECs was blunted by LS exposure and by a cathepsin L inhibitor but not by cathepsin B and S inhibitors, whereas a cathepsin K inhibitor had a minor effect. Cathepsin L siRNA knocked down cathepsin L expression, gelatinase, and elastase activity in OS and static MAECs. A partial reduction of cathepsin B protein raised the possibility that the siRNA effect on the matrix protease activity could have been attributable to cathepsin L or B. Cathepsin B activity study using the synthetic peptide showed it was not regulated by shear. Key Words: shear stress Ⅲ cathepsin Ⅲ elastase Ⅲ gelatinase Ⅲ atherosclerosis V ascular endothelial cells are constantly exposed to fluid shear stress, the frictional force generated by blood flow over the vascular endothelium. The importance of shear stress in vascular biology and pathophysiology has been highlighted by the focal development patterns of atherosclerosis in hemodynamically defined regions. For example, the regions of branched and curved arteries exposed to disturbed flow conditions including oscillatory and low mean shear stresses (OS) correspond to atheroprone areas. In contrast, straight arteries exposed to pulsatile high levels of laminar shear stress (LS) are relatively well protected from atherosclerotic plaque development. 1 Changes in blood flow have been shown to be a critical factor inducing arterial remodeling. 1-7 Increases in arterial wall shear stress prevent vascular remodeling leading to thickening of the vascular wall and inflammation, 2 whereas decreases in arterial wall shear stress promote arterial remodeling and inflammation. 2,3 Additionally, low wall shear stress leads to degradation of the internal elastic lamina (IEL). 5 Despite these findings, the underlying mechanisms by which shear regulates proteases degrading vessel wall matrix and IEL are not well described. Although there is a report demonstrating that shear regulates matrix metalloproteases (MMPs) in endothelial cells, 8 it is not clear whether other proteases are also regulated by shear. Conclusions-TheseCathepsins are the papain family of cysteine proteases which degrade elastin in addition to collagen. 9 Unlike MMPs, the role for cathepsins in blood vessel remodeling and cardiovascular disease has been understudied until recently. Cathepsins K, L, and S, potent elastinolytic proteases, have been identified in atheroscleroti...

show abstract

Lack of the Cysteine Protease Inhibitor Cystatin C Promotes Atherosclerosis in Apolipoprotein E–Deficient Mice

Cited by 98 publications

References 32 publications

Urinary Cystatin C as a Potential Risk Marker for Cardiovascular Disease and Chronic Kidney Disease in Patients with Obesity and Metabolic Syndrome

Urinary Cystatin C as a Potential Risk Marker for Cardiovascular Disease and Chronic Kidney Disease in Patients with Obesity and Metabolic Syndrome

Serum Cystatin C Is Related to Pulse Wave Velocity Even in Subjects with Normal Serum Creatinine

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Contact Info

Product

Resources

About