High levels of cathepsin D and cystatin B are associated with increased risk of coronary events

Objective The majority of acute coronary syndromes are caused by plaque ruptures. Proteases secreted by macrophages play an important role in plaque ruptures by degrading extracellular matrix proteins in the fibrous cap. Matrix metalloproteinases have been shown to be markers for cardiovascular disease whereas the members of the cathepsin protease family are less studied. Methods Cathepsin D, cathepsin L and cystatin B were measured in plasma at baseline from 384 individuals who developed coronary events (CEs), and from 409 age-matched and sex-matched controls from the Malmö Diet and Cancer cardiovascular cohort. Results Cathepsin D (180 (142–238) vs 163 (128–210), p<0.001), cathepsin L (55 (44–73) vs 52 (43–67), p<0.05) and cystatin B levels (45 (36–57) vs 42 (33–52), p<0.001) were significantly increased in CE cases compared to controls. In addition, increased cathepsin D (220 (165–313) vs 167 (133–211), p<0.001), cathepsin L (61 (46–80) vs 53 (43–68), p<0.05) and cystatin B (46 (38–58) vs 43 (34–54), p<0.05) were associated with prevalent diabetes. Furthermore, cathepsin D and cystatin B were increased in smokers. The HRs for incident CE comparing the highest to the lowest tertile(s) of cathepsin D and cystatin B were 1.34 (95% CI 1.02 to 1.75) and 1.26 (95% CI 1.01 to 1.57), respectively, after adjusting for age, sex, low-density lipoprotein/high-density lipoprotein ratio, triglycerides, body mass index, hypertension and glucose, but these associations did not remain significant after further addition of smoking to the model. In addition, cathepsin D was increased in incident CE cases among smokers after adjusting for cardiovascular risk factors. Conclusions The associations of cathepsin D and cystatin B with future CE provide clinical support for a role of these factors in cardiovascular disease, which for cathepsin D may be of particular importance for smokers.

[1]  B. Ohlsson,et al.  PT05.1: Intake of Different Types of Red Meat, Poultry and Fish and Incident Colorectal Cancer in Women and Men - Results from the Malmö Diet and Cancer Study , 2016 .

[2]  Johan Sundström,et al.  Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts , 2015, Diabetes.

[3]  J. Stenvang,et al.  Homogenous 96-Plex PEA Immunoassay Exhibiting High Sensitivity, Specificity, and Excellent Scalability , 2014, PloS one.

[4]  L. Rivera,et al.  Macrophage Derived Cystatin B/Cathepsin B in HIV Replication and Neuropathogenesis , 2014, Current HIV research.

[5]  J. Lindholt,et al.  Plasma levels of cathepsins L, K, and V and risks of abdominal aortic aneurysms: a randomized population-based study. , 2013, Atherosclerosis.

[6]  O. Melander,et al.  High levels of cystatin C predict the metabolic syndrome: the prospective Malmö Diet and Cancer Study , 2013, Journal of internal medicine.

[7]  Masataka Nakano,et al.  Pathophysiology of atherosclerosis plaque progression. , 2013, Heart, lung & circulation.

[8]  T. Korolenko,et al.  Evaluation of serum procathepsin B, cystatin B and cystatin C as possible biomarkers of ovarian cancer , 2013, International journal of circumpolar health.

[9]  F. Vivanco,et al.  Vascular proteomics , 2013, Methods in Molecular Biology.

[10]  A. Newby.  Matrix metalloproteinase inhibition therapy for vascular diseases. , 2012, Vascular pharmacology.

[11]  T. Reinheckel,et al.  Cathepsins D and L reduce the toxicity of advanced glycation end products. , 2012, Free radical biology & medicine.

[12]  V. Vetvicka,et al.  Procathepsin D as a tumor marker, anti-cancer drug or screening agent. , 2012, Anti-cancer agents in medicinal chemistry.

[13]  W. Daniel,et al.  Carotid Plaque Vulnerability: A Positive Feedback Between Hemodynamic and Biochemical Mechanisms , 2011, Stroke.

[14]  B. Hedblad,et al.  Food patterns, inflammation markers and incidence of cardiovascular disease: the Malmö Diet and Cancer study , 2011, Journal of internal medicine.

[15]  Christofer L. Bäcklin,et al.  ProteinSeq: High-Performance Proteomic Analyses by Proximity Ligation and Next Generation Sequencing , 2011, PloS one.

[16]  Enas A. Hamed,et al.  Vasculopathy in type 2 diabetes mellitus: role of specific angiogenic modulators , 2011, Journal of Physiology and Biochemistry.

[17]  Wei Li,et al.  p53 expression in human carotid atheroma is significantly related to plaque instability and clinical manifestations. , 2010, Atherosclerosis.

[18]  R. Zeng,et al.  Quantitative analysis of secretome from adipocytes regulated by insulin. , 2009, Acta biochimica et biophysica Sinica.

[19]  C. Frélicot,et al.  Significant lower VVH7-like immunoreactivity serum level in diabetic patients: Evidence for independence from metabolic control and three key enzymes in hemorphin metabolism, cathepsin D, ACE and DPP-IV , 2009, Peptides.

[20]  Chin-Lee Wu,et al.  Cystatin B As a Tissue and Urinary Biomarker of Bladder Cancer Recurrence and Disease Progression , 2009, Clinical Cancer Research.

[21]  J. Egido,et al.  Proteomic Analysis of Circulating Monocytes Identifies Cathepsin D as A Potential Novel Plasma Marker of Acute Coronary Syndromes , 2008 .

[22]  S. Mohammed,et al.  Atorvastatin modulates the profile of proteins released by human atherosclerotic plaques. , 2007, European journal of pharmacology.

[23]  H. Jo,et al.  Laminar shear stress inhibits cathepsin L activity in endothelial cells (EC) , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[24]  P. Libby,et al.  Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells. , 2006, Atherosclerosis.

[25]  R. Pauwels,et al.  Matrix Metalloproteinase-12 and Cathepsin D Expression in Pulmonary Macrophages and Dendritic Cells of Cigarette Smoke-Exposed Mice , 2005, International Archives of Allergy and Immunology.

[26]  Jean-Daniel Zucker,et al.  Cathepsin S, a novel biomarker of adiposity: relevance to atherogenesis , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  M. Trinkaus,et al.  Cathepsins B and L and their inhibitors stefin B and cystatin C as markers for malignant progression of benign meningiomas. , 2005, The International journal of biological markers.

[28]  Wei Li,et al.  Increased Expression and Translocation of Lysosomal Cathepsins Contribute to Macrophage Apoptosis in Atherogenesis , 2004, Annals of the New York Academy of Sciences.

[29]  G. Opiteck,et al.  In Vitro Biomarker Discovery for Atherosclerosis by Proteomics* , 2004, Molecular & Cellular Proteomics.

[30]  S. Antonarakis,et al.  The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion , 2003, Cytogenetic and Genome Research.

[31]  H. Du,et al.  Lysosomal Enzymes Are Released From Cultured Human Macrophages, Hydrolyze LDL In Vitro, and Are Present Extracellularly in Human Atherosclerotic Lesions , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[32]  A. Hamsten,et al.  Differential expression of cysteine and aspartic proteases during progression of atherosclerosis in apolipoprotein E-deficient mice. , 2002, The American journal of pathology.

[33]  G. Berglund,et al.  Food patterns and components of the metabolic syndrome in men and women: a cross-sectional study within the Malmö Diet and Cancer cohort. , 2001, American journal of epidemiology.

[34]  P. Nilsson,et al.  Relation between insulin resistance and carotid intima‐media thickness and stenosis in non‐diabetic subjects. Results from a cross‐sectional study in Malmö, Sweden , 2000, Diabetic medicine : a journal of the British Diabetic Association.

[35]  P. Libby,et al.  Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. , 1998, The Journal of clinical investigation.

[36]  S. Kira,et al.  Cathepsin L activity is increased in alveolar macrophages and bronchoalveolar lavage fluid of smokers. , 1993, The American review of respiratory disease.

[37]  G. Berglund,et al.  Design and feasibility , 1993 .

[38]  G. Berglund,et al.  The Malmo Diet and Cancer Study. Design and feasibility. , 1993, Journal of internal medicine.

[39]  H. Robenek,et al.  In situ immunolocalization of lipoproteins in human arteriosclerotic tissue. , 1993, Arteriosclerosis and thrombosis : a journal of vascular biology.

[40]  R. Nixon,et al.  Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[41]  M. Lesser,et al.  Cathepsin D activity is increased in alveolar macrophages and bronchoalveolar lavage fluid of smokers. , 1989, The American review of respiratory disease.

[42]  E. Ring,et al.  Secretion and localization of cathepsin D in synovial tissues removed from rheumatoid and traumatized joints. An immunohistochemical study. , 1976, Arthritis and rheumatism.