Elastin Degradation Is Associated With Progressive Aortic Stiffening and All-Cause Mortality in Predialysis Chronic Kidney Disease

Brighton and Sussex University Hospitals National Health Service Trust, Brighton, United Kingdom.
Hypertension (Impact Factor: 6.48). 03/2012; 59(5):973-8. DOI: 10.1161/HYPERTENSIONAHA.111.187807
Source: PubMed


In the large conduit arteries, elastin is important in maintaining vascular compliance. Studies in animal models suggest that elastin degradation may promote arteriosclerotic vascular changes. There is already a well-established link between aortic stiffening and mortality in the general population and in patients undergoing dialysis. Elastin degradation is mediated by several proteases, including matrix metalloproteinase 2 and cathepsin S. Elastin turnover may be inferred by measuring serum levels of elastin-derived peptides. We analyzed the serum concentration of these biomarkers, their endogenous inhibitors, and aortic pulse wave velocity in 200 patients with stages 3 and 4 chronic kidney disease and then serially in a subgroup of 65 patients over 36 months. Serum matrix metalloproteinase 2, cathepsin S, and elastin-derived peptide levels were independently associated with baseline aortic pulse wave velocity and changes in stiffness over the follow-up period. Higher matrix metalloproteinase 2 and elastin-derived peptide levels were also independently associated with preexisting cardiovascular disease. In multivariable Cox regression, higher serum elastin-derived peptide levels were independently associated with increased all-cause mortality (hazard ratio per SD increase=1.78; P=0.021). In predialysis chronic kidney disease, elastin degradation is an important determinant of arterial stiffness and is associated with all-cause mortality.

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Available from: Edward R Smith, Feb 15, 2015
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    • "We reported that cathepsin K is overexpressed in the intracoronary artery of hypertensive heart failure tissues.21 Several clinical studies have shown that patients with atherosclerosis-related diabetes, aneurysm and chronic kidney disease had increased levels of serum cathepsins S or L.15,22,23 These data suggested that cathepsins levels are associated with atherosclerosis-based cardiovascular disease. However, there is limited information regarding the relationship between circulating cathepsin K and coronary artery disease (CAD). "
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    ABSTRACT: Purpose Cathepsin K is a potent collagenase implicated in human and animal atherosclerosis-based vascular remodeling. This study examined the hypothesis that serum CatK is associated with the prevalence of coronary artery disease (CAD). Materials and Methods Between January 2011 and December 2012, 256 consecutive subjects were enrolled from among patients who underwent coronary angiography and percutaneous coronary intervention treatment. A total of 129 age-matched subjects served as controls. Results The subjects' serum cathepsin K and high sensitive C-reactive protein (hs-CRP) and high-density lipoprotein cholesterol were measured. The patients with CAD had significantly higher serum cathepsin K levels compared to the controls (130.8±25.5 ng/mL vs. 86.9±25.5 ng/mL, p<0.001), and the patients with acute coronary syndrome had significantly higher serum cathepsin K levels compared to those with stable angina pectoris (137.1±26.9 ng/mL vs. 102.6±12.9 ng/mL, p<0.001). A linear regression analysis showed that overall, the cathepsin K levels were inversely correlated with the high-density lipoprotein levels (r=-0.29, p<0.01) and positively with hs-CRP levels (r=0.32, p<0.01). Multiple logistic regression analyses shows that cathepsin K levels were independent predictors of CAD (odds ratio, 1.76; 95% confidence interval, 1.12 to 1.56; p<0.01). Conclusion These data indicated that elevated levels of cathepsin K are closely associated with the presence of CAD and that circulating cathepsin K serves a useful biomarker for CAD.
    Full-text · Article · Jul 2014 · Yonsei Medical Journal
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    • "Reports from the literature support this postulate. In adults with chronic kidney diseases, increased serum levels of cathepsin S and MMP-2 are associated with aortic stiffening [64]. In newborn mice, cathepsin S deficiency prevents elastin degradation and profibrotic changes, and protects from O2-induced lung injury [65]. "
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    ABSTRACT: Neonatal high-oxygen exposure leads to elevated blood pressure, microvascular rarefaction, vascular dysfunction and arterial (aorta) rigidity in adult rats. Whether structural changes are present in the matrix of aorta wall is unknown. Considering that elastin synthesis peaks in late fetal life in humans, and early postnatal life in rodents, we postulated that transient neonatal high-oxygen exposure can trigger premature vascular remodelling. Sprague Dawley rat pups were exposed from days 3 to 10 after birth to 80% oxygen (vs. room air control) and were studied at 4 weeks. Blood pressure and vasomotor response of the aorta to angiotensin II and to the acetylcholine analogue carbachol were not different between groups. Vascular superoxide anion production was similar between groups. There was no difference between groups in aortic cross sectional area, smooth muscle cell number or media/lumen ratio. In oxygen-exposed rats, aorta elastin/collagen content ratio was significantly decreased, the expression of elastinolytic cathepsin S was increased whereas collagenolytic cathepsin K was decreased. By immunofluorescence we observed an increase in MMP-2 and TIMP-1 staining in aortas of oxygen-exposed rats whereas TIMP-2 staining was reduced, indicating a shift in the balance towards degradation of the extra-cellular matrix and increased deposition of collagen. There was no significant difference in MMP-2 activity between groups as determined by gelatin zymography. Overall, these findings indicate that transient neonatal high oxygen exposure leads to vascular wall alterations (decreased elastin/collagen ratio and a shift in the balance towards increased deposition of collagen) which are associated with increased rigidity. Importantly, these changes are present prior to the elevation of blood pressure and vascular dysfunction in this model, and may therefore be contributory.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "This degradation of elastin may occur slowly over decades, but inflammatory diseases affecting elastic tissue degradation may accelerate this process. Therefore, DES and IDS have been proposed as biomarkers useful to selectively monitor the degradation of elastin in diseases such as chronic obstructive pulmonary disease (COPD), abdominal aortic aneurism (AAA), and chronic kidney disease (CKD) [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]. "
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    ABSTRACT: Elastin is a one of the major extracellular matrix proteins associated with connective tissue. Its degradation leads to the liberation of the unique amino acids desmosine and isodesmosine. These have shown utility as biomarkers of elastin break down for disease progression, patient stratification and drug efficacy. So far, the quantitation of desmosines in plasma is hampered by complex sample preparation. We demonstrate an improved and simplified procedure for detecting both free and total desmosines. The method is based on spiking with a deuterium labeled desmosine standard, ethanol precipitation, propionylation, HPLC-separation and selection reaction monitoring (SRM) mass spectrometry. The performance of the assay is illustrated by comparing the levels of free and total desmosines in normal healthy plasma and that from patients diagnosed with chronic obstructive pulmonary disease (COPD). A conserved ratio of 1:3 between free to total desmosine was found. The determination of free desmosine has a higher accuracy than that of total desmosine, therefore being the method of choice when plasma volume is limiting. Finally, we show that the plasma desmosine concentration correlates with age and body mass index.
    Full-text · Article · Feb 2013 · Analytical Biochemistry
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