Skip Navigation


Age and Ageing Advance Access originally published online on March 10, 2008
Age and Ageing 2008 37(3):318-323; doi:10.1093/ageing/afn039
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
37/3/318    most recent
afn039v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Paczek, L.
Right arrow Articles by Bartlomiejczyk, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Paczek, L.
Right arrow Articles by Bartlomiejczyk, I.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © The Author 2008. Published by Oxford University Press on behalf of the British Geriatrics Society.

Trypsin, elastase, plasmin and MMP-9 activity in the serum during the human ageing process

Leszek Paczek, Wanda Michalska and Irena Bartlomiejczyk

Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, 02-006 Warsaw, Nowogrodzka 59, Poland

Address correspondence to: Leszek Paczek. Tel: +48 (0)22 502 16 41; Fax: +48 (0) 22 502 21 27. Email: leszekpaczek{at}onet.pl; rektor{at}rektorat.amwaw.edu.pl


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Key points
 Conflicts of interests
 Funding
 Supplementary data
 References
 
Objective: the aim of this work was to define the influence of the ageing process on the activity of proteolytic enzymes, such as trypsin, elastase, plasmin and active MMP-9 concentration, as well as the inhibitor {alpha} 1-antitrypsin. Moreover, we assessed associations between enzyme activity and selected clinical and biochemical parameters.

Methods: healthy normotensive volunteers (n = 60, 30 women) aged 20–82 years were split into subgroups: young (aged 20–22), middle-aged (49–52) and elderly (77–82). Serum enzyme activity was assessed using fluorometric methods.

Results: overall, active MMP-9 concentration and trypsin activity decreased with age, and {alpha}1-antitrypsin concentration and plasmin activity increased. Activity of elastase increased with age when compared to the young age group. An inverse correlation was identified between MMP-9 concentration and BMI and a direct correlation found between BMI and elastase, plasmin activity and {alpha}1-antitrypsin concentration. In the middle-aged group, glucose correlated directly with trypsin activity and inversely with MMP-9 concentration. Trypsin activity and MMP-9 concentration correlated inversely with cholesterol concentration and plasmin and elastase activity, and the {alpha}1-antitrypsin concentration correlated with cholesterol concentration in the overall group.

Conclusions: the results confirm the influence of the ageing process on the activity of serum proteolytic enzymes. The activity of individual proteolytic enzymes in the serum changes with age.

Keywords: ageing, trypsin, plasmin, elastase, metalloproteinases


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Key points
 Conflicts of interests
 Funding
 Supplementary data
 References
 
In humans, ageing is a physiological process of a gradually advancing accumulation of characteristic structural changes in cells, tissues and organs. The changes cause functional disorders and contribute to the disability of adaptation skills, an increased susceptibility to illnesses and a growing probability of death [1]. Ageing is characterised by an increase in the amount of cross-links in proteins and the development of aggregates resistant to the activity of proteolytic enzymes, which leads to the accumulation [2]. A change in the susceptibility of proteins to proteolysis and, above all, damage to proteolytic systems responsible for the elimination of these proteins, are seen as the causes of this occurrence [3]. A few separate proteolytic systems take part in the intra-cellular degradation of proteins. They differ in sub-cellular localisation and substrate specificity.

Plasmin, trypsin and elastase belong to the serine protease group. Serine proteases are proteolytic enzymes that contain a highly reactive serine residue. Plasmin intensifies the degradation of the extra-cellular matrix proteins directly and indirectly by activating the matrix metalloproteinases (MMPs) MMP-3, MMP-9, MMP-1 and MMP-2 [4, 5]. The accumulation of the products of plasmin breakdown and extra-cellular vessel wall matrix degradation plays an important role in the pathogenesis of blood vessel ageing [6]. Moreover, an increase in concentrations of plasmin–{alpha}2-antiplasmin complexes has been observed during the process of ageing and in people with acute coronary syndrome [7].

Trypsin is synthesised by the exocrine pancreas in the form of a proenzyme, and in serum, it is associated with the protease inhibitors {alpha}1-antitrypsin and {alpha}2-macroglobulin. The trypsin–{alpha}2-macroglobulin complex is not degraded by other proteases and at the same time retains its enzymatic activity [8]. Trypsin hydrolyses both proteins present in food and extra-cellular matrix proteins by indirectly activating latent forms of many MMPs, including MMP-9, MMP-8 and MMP-1 [9, 10].

Elastase works in inter-cellular spaces and a micro-environment and is secreted by smooth muscle cells, fibroblasts, endothelium cells and white blood cells [11]. The substrates for granulocytic elastase are both extra-cellular matrix proteins such as elastin, fibronectin, laminin, types III, IV, VI collagen and proteoglycans, and also plasma proteins, including immunoglobulins, coagulation factors, {alpha}2-antiplasmin and bacterial proteins [12]. This enzyme digests the elastic fibres present in the arterial vessel walls, which results in an increased concentration of elastin degradation products in the serum. The elastic fibres are degraded during ageing and atherogenesis [13, 14].

The {alpha}1-antitrypsin, with a molecular mass of 51,000 kD, is an important inhibitor of serine proteases in the serum. It is synthesised by hepatocytes and macrophages as well as by epithelial cells in the bronchial tubes and is responsible for 90% of antitrypsin serum activity; however, its main function is to halt the elastase freed from the granulation of neutrophils [15].

MMPs are endopeptidases involved in many physiological and pathological processes, including the pathogenesis of various malignancies [16]. Moreover, MMP-9 catalyses post-translational activation of cytokines such as IL-1β, TNF-{alpha}, TGF-β and chemokines [17, 18].

The aim of this work was to assess the activity of proteolytic enzymes during human ageing and simultaneously to attempt to define the role of proteolytic enzymes in the development of the ageing process.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Key points
 Conflicts of interests
 Funding
 Supplementary data
 References
 
The study involved 60 healthy participants (30 women) aged 20–82 years. Participants had no history of chronic inflammatory diseases, chronic glomerular kidney inflammation, systemic connective tissue diseases, joint diseases, neurological diseases, neoplastic diseases, acute coronary syndromes or diabetes, and gave their written consent to take part in the study. History of tobacco smoking, alcohol consumption and arterial blood pressure was assessed. The study was conducted with approval by the Bioethical Commission at the Medical University of Warsaw (no. KB/248/2003). Study volunteers were divided into age subgroups: young (average age: 21.3 years; age range: 20–22), middle-aged (average age: 50.8; age range: 49–52) and elderly (average age: 79.7; age range: 77–82). Each subgroup had 10 women and 10 men. The study material was fasting venous blood from the cubital vein. For assessment of serum MMP-9, trypsin, elastase activity and {alpha}1-antitrypsin concentration, 30 min after the blood draw serum was removed after a 10-min centrifugation at 1, 000 x g in 4°C. Blood for measuring plasmin activity was drawn in heparin vials and centrifuged for 10 min at 1, 000 x g in 4°C. Serum and heparinised plasma samples were kept in –70°C until analysis. Blood was also collected for morphology and basic biochemical studies, such as ionogram, alkali reserve, transaminase and bilirubin levels, creatinine concentration, total cholesterol concentration, proteinogram, C reactive protein (CRP), concentration of fasting glucose and lipase concentration. BMI was assessed and arterial blood pressure measured.

Analytical methods
The activity of trypsin was studied using the fluorometric method, applying the Z–Arg–AMC HCl substrate (Bachem, Biochemica GmbH Heidelberg, Germany). The samples were incubated in an activating buffer (50 mM TES/0.4 mM Z–Arg–AMC HCl, pH 8.0) for 60 min at room temperature and then measured on a spectrofluorometer (Perkin-Elmer LS-50B, USA) at an activation light wavelength {lambda} = 355 nm and emitted light wavelength {lambda} = 460 nm. A dilution of the AMC mother solution (20 mM in 5% CH3COOH) in TES buffer in the range of 0.312–10 µM constituted the standard curve. Enzymatic activity is given as IU/l [19].

Elastase activity was also assessed using the fluorometric method with an Ac–Ala–Ala–Pro–Ala–AMC substrate (Bachem, Biochemica GmbH Heidelberg, Germany) [19], as was plasmin activity using the Boc–Val–Leu–Lys–AMC AcOH substrate (Bachem, Biochemica GmbH Heidelberg, Germany) [20].

The concentration of the active form of serum MMP-9 was measured by fluorometry with the Fluorokine E Active MMP-9 reagent set (R&D Systems, Wiesbaden, Germany). A fluorogenic substrate was used at 1 mM in DMSO, and recombined human proenzyme MMP-9 was the standard. Para-aminophenyl mercury acetate was the activator of the MMP-9 proenzyme. After a 20-h incubation at 37°C, the intensity of fluorescence was read on the spectrofluorometer (Perkin-Elmer LS-50B, Seer Green, UK) at the activation light wavelength {lambda} = 340 nm and emission light wavelength {lambda} = 405 nm. The concentration of active enzyme is given as µg/l.

Statistical methods
Statistical calculations were made using SPSS version 12.0 PL, made available by the Warsaw University Department of Psychology. To perform the statistical assessment of the age groups of men and women, a student's t-test was applied for separate samples. In cases of three or more comparable groups, a simple single-factor variation analysis was used to assess the relevance of the differences, using the Smallest Relevant Difference test. The assessment of the intensity of the connection between the variables was performed using the Tau-Kendall correlation coefficient. The results were considered relevant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Key points
 Conflicts of interests
 Funding
 Supplementary data
 References
 
Table 1 shows basic clinical and laboratory parameters. All results of biochemical and haematology studies fell within the reference value range. Clinical and biochemical data were compared in the studied subgroups, and P-values are given in the table, as well.


View this table:
[in this window]
[in a new window]

  		Table 1. Basic clinical and laboratory parameters

 
Table 2 shows proteolytic enzyme activity. The data were compared in the studied subgroups, and P-values are given in the table. There was overall dependence between proteolytic enzyme activity and the selected factors (aged 20–82).


View this table:
[in this window]
[in a new window]

  		Table 2. Proteolytic enzyme activities and serum concentration of MMP-9 and of {alpha}1-antitrypsin

 
Figure 1A–D shows the significant statistical correlations among MMP-9 concentration, elastase activity, serum {alpha}1-antitrypsin concentration, plasmin activity and BMI in the study group. A statistically important correlation was identified among elastase activity, the MMP-9 concentration, serum {alpha}1-antitrypsin concentration, plasmin and systolic and diastolic blood pressure (Appendix 1A–D, 2A–C, see the journal's website http://www.ageing.oxfordjournals.org). No important correlation was noted between blood pressure and serum trypsin activity. A statistically important dependence was identified between glucose concentration and MMP-9 concentration and serum {alpha}1-antitrypsin concentration (Appendix 3A–B, see the journal's website http://www.ageing.oxfordjournals.org). No significant association was identified between serum glucose concentration and activities of elastase, plasmin or trypsin. Significant statistical correlations were identified between the activity of elastase, trypsin, plasmin, MMP-9 concentration, and {alpha}1-antitrypsin and the serum total cholesterol (Appendix 4A–E, see the journal's website http://www.ageing.oxfordjournals.org).


Figure 1
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1. Concentration of MMP-9 (A) and {alpha}1-antitrypsin (C) and activity of elastase (B) in the serum and activity of plasmin (D) in the plasma in relation to BMI.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Key points
 Conflicts of interests
 Funding
 Supplementary data
 References
 
The exact mechanisms leading to the ageing of an organism remains unknown, but there is increasing evidence of the role of proteolytic enzymes in the pathology of diseases that accompany age, such as atheromatosis, cataracts, degenerative joint disease, neoplasms and cardiovascular system diseases. The aim of this work was to define the influence of the process of ageing on the proteolytic enzyme activity in the serum. Many authors have found a role, for example, for elastase in processes associated with ageing, including its role in atherogenesis and atheromatotic changes [21], aneurysms [22], and ischaemic heart disease [23].

On the basis of the recent reports in the literature [22, 23] and on the current results, it can be inferred that a decrease in serum elastase activity (when compared between the middle-aged and elderly group) and increase in serine protease inhibitor concentration may serve as a marker of arterial vessel wall inflammatory change. Such changes are characteristic of atheromatosis, a chronic process that develops with age. Available data lead to the hypothesis that intensive secretion of elastase in vessel walls undergoing atheromatosis may lead to its loss and to decreased serum activity. Our current results suggest that an increase in {alpha}1-antitrypsin concentration with age halts elastase activity in the serum.

The middle-aged group exhibited a statistically significant higher trypsin activity than the elderly group. A study assessing the age-dependent activity of trypsin in brain structures found that activity decreases with age in the cortex, cerebellum, striatum and pale globe of mice and rats in old age compared to young mice and rats. Changes in the activity of this enzyme may play a role in the pathogenesis of Parkinson's disease [24]. The decrease in trypsin activity in the serum with age may arise from an increase in {alpha}1-antitrypsin activity, the serine protease inhibitor.

Plasmin is the main enzyme involved in the fibrinolysis process. In cardiovascular diseases, D-dimer concentrations are diagnostically quite relevant. D-dimer concentration increases with age; higher concentrations in middle-aged men are associated with increased risk of ischaemic heart disease, and the age increase is also statistically relevant for people with atheromatosis. High D-dimer levels have also been observed in atheromatosis of coronary, cerebral and peripheral arteries [25]. The current results and previous findings suggest that the increase in plasma plasmin activity reflects increased activation of blood clotting and fibrinolysis and may serve as an atheromatosis development marker and marker for cardiovascular system diseases, both characteristic illnesses of old age.

We also identified a statistically relevant inverse relationship between both systolic and diastolic pressure and serum MMP-9 concentration. With increase in arterial pressure, the MMP-9 concentration decreased. However, the relationship of elastase, plasmin activity and the {alpha}1-antitrypsin concentration with systolic and diastolic pressure was positive. No correlation was noted between arterial pressure and trypsin activity.

Other studies have demonstrated a relationship between elastase and MMP-9 activity and atheromatosis (see [26, 27]). These enzymes take an active part in the remodelling of vessel walls and play an important role in the pathogenesis of cardiovascular system diseases. On the basis of previous reports and current findings, it can be inferred that proteolytic enzymes are actively involved in the remodelling of vessel walls, causing stiffness in them and contributing to the development of hypertension.

A directly proportional dependence was found between BMI and the activity of elastase and {alpha}1-antitrypsin, but no relationship between BMI and trypsin activity was found. One large study of 1,400 patients with cardiovascular disease demonstrated that the activity of elastase in the serum was directly proportional to the BMI and glucose and inverse proportional to triglycerides, while the concentration of {alpha}1-antitrypsin was inversely correlated with total cholesterol concentration. The authors concluded that the remodelling of vessel walls depends not only on the degradation of elastin but also on lipid metabolism [28].

In addition, an inverse relationship between glucose concentration and MMP-9 concentration was identified, as was a directly proportional dependence between {alpha}1-antitrypsin concentration and glucose concentration. No relationship between glucose concentration and the activity of the other enzymes was found. Other studies have found links between ageing, decreased metalloproteinase and proteolytic enzyme activity, and pathogenesis of renal fibrosis. One study found that the decreased activity of proteolytic enzymes is conducive to protein accumulation of renal glomeruli of the extra-cellular matrix, which may be one of the causes of renal failure [29, 30]. Another group showed in vitro that trypsin decreases protein degradation, corrects cell proliferation, and increases protein synthesis and its content in the cell. On the basis of their results, these authors hypothesised that trypsin decreases glycolysation of proteins on cell surface. Trypsin decreases the advanced glycation end products–receptor for advanced glycation end products interaction due to cleavage of the external domain of receptor for advanced glycation end products [31, 32]. These findings suggest that the decrease in the activity of proteolytic enzymes with age may influence the pathogenesis of kidney diseases.

The current results confirm the influence of the ageing process on the activity of proteolytic enzymes in the serum. With age, the activity of individual proteolytic enzymes in the serum changes.


   Key points
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Key points
Conflicts of interests
 Funding
 Supplementary data
 References
 

  • Concentration of active MMP-9 and activity of trypsin decreased with age.
  • Plasmin activity and concentration of {alpha}1-antitrypsin increased during ageing process.
  • Significant correlation was identified between activity of the proteolytic enzymes and clinical and biochemical parameters.


   Conflicts of interests
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Key points
 Conflicts of interests
Funding
 Supplementary data
 References
 
No conflicts of interest


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Key points
 Conflicts of interests
 Funding
Supplementary data
 References
 
The work has been written within the research project framework reg. no. 2 PO5A 203 29 from Ministry of Science and Higher Education.


   Supplementary data
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Key points
 Conflicts of interests
 Funding
 Supplementary data
References
 
Supplementary data for this article are available online at http://ageing.oxfordjournals.org.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Key points
 Conflicts of interests
 Funding
 Supplementary data
 References
 

  1. Harman D. Free radical involvement in aging. Pathophysiology and therapeutic implications. Drugs Aging (1993) 3:60–80.[Web of Science][Medline]
  2. Ritthaler U, Deng Y, Zhang Y. Expression of receptors for advanced glycation end products in peripheral occlusive vascular disease. Am J Pathol (1995) 146:688–94.[Abstract]
  3. Cuervo AM, Dice JF. Lysosomes a meeting point of proteins, chaperones and proteases. J Mol Med (1998) 76:6–12.[CrossRef][Web of Science][Medline]
  4. Syrovets T, Simmet T. Novel aspects and new roles for the serine protease plasmin. Cell Mol Life Sci (2004) 61:873–85. Review.[CrossRef][Web of Science][Medline]
  5. Sakkinen PA, Cushman M, Psaty BM, et al. Relationship of plasmin generation to cardiovascular disease risk factor in elderly men and women. Arterioscler Thromb Vasc Biol (1999) 19:499–504.[Abstract/Free Full Text]
  6. Schneiderman J, Bordin GM, Engelberg I, et al. Expression of fibrinolytic genes in atherosclerotic abdominal aortic aneurysm wall. A possible mechanism for aneurysm expansion. J Clin Invest (1995) 96:639–45.[Web of Science][Medline]
  7. Thompson SG, Kienast J, Pyke SD, et al, European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med. (1995) 332:635–41.[Abstract/Free Full Text]
  8. Barrett AJ, Starkey PM. The interaction of {alpha}2M with proteases. Biochem J (1973) 133:709–24.[Web of Science][Medline]
  9. Umenishi F, Yasumitsu H, Ashida Y, et al. Purification and properties of extracellular matrix-degrading metalloproteinase overproduced by Rous sarcoma virus-transformed rat liver cell line, and its identification as transin. J Biochem (1990) 108:537–43.[Abstract/Free Full Text]
  10. Devarajan P, Johnston JJ, Ginsberg SS, et al. Structure and expression of neutrophil gelatinase cDNA: identity with type IV collagenase from HT 1080 cells. J Biol Chem (1992) 267:25228–32.[Abstract/Free Full Text]
  11. Robert L, Jacob MP, Frances C, et al. Interaction between elastin and elastases and its role in the aging of the arterial wall, skin and other connective tissues. Mech Ageing Dev (1984) 28:155–66. Review.[CrossRef][Web of Science][Medline]
  12. Beynon RJ, Bond JS. The Practical Approach Series. Rickwood D, Hames BD, eds. (1996) New York: Oxford University Press Inc. 2–3. Series Editors. Proteolytic enzymes (a practical approach).
  13. Bizbiz L, Alperovitch A, Robert L, The EVA study. Aging of the vascular wall: serum concentration of elastin peptides and elastase inhibitors in relation to cardiovascular risk factors. Atherosclerosis (1997) 131:73–8.[CrossRef][Web of Science][Medline]
  14. Robert L. Aging of vascular wall and atherogenesis, role of the elastin-laminin receptor. Atherosclerosis (1996) 123:169–79.[CrossRef][Medline]
  15. Lomas DA, Mahadeva R. Alpha 1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest (2002) 110:1585–90.[CrossRef][Web of Science][Medline]
  16. Tomita T, Iwata K. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in some endocrine organs and their tumors. Endocr Pathol (1999) 10:15–26.[CrossRef][Web of Science]
  17. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev (2000) 14:163–76.[Abstract/Free Full Text]
  18. Gearing AJ, Beckett p, Christodoulou M, et al. Processing of tumor necrosis factor-alfa precursor by metalloproteinases. Nature (1994) 370:555–7.[CrossRef][Medline]
  19. Zimmernam M, Ashe B, Yurewicz EC, et al. Sensitive assays for trypsin, elastase and chymotrypsin using new fluorogenic substrate. Anal Biochem (1977) 78:47–51.[CrossRef][Web of Science][Medline]
  20. Smith RE, Bissel ER, Mithell AR, et al. Direct photometric and fluorometric assay of proteinases using substrates containing 7-amido-4-trifluoromethylcoumarin. Thromb Res (1980) 17:393–402.[CrossRef][Web of Science][Medline]
  21. Balo J. International Review of Connective Tissue Research. Hall DA, ed. (1963) Vol. I. New York: Academic Press. 241–306. Connective tissue changes in atherosclerosis.
  22. Aassar SO, Fujiwara NH, Marx WF, et al. Aneurysm growth, elastinolysis, and attempted doxycycline inhibition of elastase-induced aneurysms in rabbits. J Vasc Interv Radiol (2003) 14:1427–32.[Web of Science][Medline]
  23. Barolet AW, Nili N, Cheema A, et al. Arterial elastase activity after balloon angioplasty and effects of elafin, an elastase inhibitor. Arterioscler Thromb Vasc Biol (2001) 21:1269–74.[Abstract/Free Full Text]
  24. Zeng BY, Medhurst AD, Jackson M, et al. Proteasomal activity in brain differs between species and brain regions and changes with age. Mech Ageing Dev (2005) 126:760–6.[CrossRef][Web of Science][Medline]
  25. Strano A, Hoppensteadt D, Walenga JM, et al. Plasma levels of the markers of coagulation and fibrinolysis arterial disease. Semin Thromb Hemost (1996) 23(Suppl. 1):35–40.
  26. Godin D, Ivan E, Johnson C, et al. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation (2000) 102:2861–6.[Abstract/Free Full Text]
  27. Longo GM, Xiong W, Greiner TC, et al. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest (2002) 110:625–32.[CrossRef][Web of Science][Medline]
  28. Bonithon-Kopp C, Touboul PJ, Berr C, et al. Factors of carotid arterial enlargement in a population aged 59 to 71 years. Stroke (1996) 27:654–60.[Abstract/Free Full Text]
  29. Schaefer L, Lorenz T, Daemmrich J, et al. Role of proteinases in renal hypertrophy and matrix accumulation. Nephrol Dial Transplant (1995) 10:801–7.[Abstract/Free Full Text]
  30. Huang S, Schaefer RM, Reisch S, et al. Suppressed activities of cathepsins and metalloproteinases in the chronic model of puromycin aminonucleoside nephrosis. Kidney Blood Press Res (1999) 22:121–7.[CrossRef][Web of Science][Medline]
  31. Schmidt AM, Hori O, Brett J, et al. Cellular receptors for Advanced Glycation End Products. Implication for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lensions. Arterioscler Thromb (1994) 14:1521–8.[Abstract/Free Full Text]
  32. Yarnell JW, Sweetnam PM, Rumley A, et al. Life style and hemostatic risk factor for ischemic heart disease. Arterioscler Thromb Vasc Biol (2000) 20:271–9.[Abstract/Free Full Text]
Received 21 March 2007; accepted in revised form 1 November 2007.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
37/3/318    most recent
afn039v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Paczek, L.
Right arrow Articles by Bartlomiejczyk, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Paczek, L.
Right arrow Articles by Bartlomiejczyk, I.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?