Measurement of CO3-610, a Potential Liver Biomarker Derived from Matrix Metalloproteinase-9 Degradation of Collagen Type III, in a Rat Model of Reversible Carbon-Tetrachloride-Induced Fibrosis

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Abdominal aortic calcification quantified by the Morphological Atherosclerotic Calcification Distribution (MACD) index is associated with features of the metabolic syndrome

<p>Abstract</p> <p>Background</p> <p>Abdominal aortic calcifications (AAC) predict cardiovascular mortality. A new scoring model for AAC, the Morphological Atherosclerotic Calcification Distribution (MACD) index may contribute with additional information to the commonly used Aortic Calcification Severity (AC24) score, when predicting death from cardiovascular disease (CVD). In this study we investigated associations of MACD and AC24 with traditional metabolic-syndrome associated risk factors at baseline and after 8.3 years follow-up, to identify biological parameters that may account for the differential performance of these indices.</p> <p>Methods</p> <p>Three hundred and eight healthy women aged 48 to 76 years, were followed for 8.3 ± 0.3 years. AAC was quantified using lumbar radiographs. Baseline data included age, weight, blood pressure, blood lipids, and glucose levels. Pearson correlation coefficients were used to test for relationships.</p> <p>Results</p> <p>At baseline and across all patients, MACD correlated with blood glucose (r²= 0.1, P< 0.001) and to a lesser, but significant extent with traditional risk factors (p < 0.01) of CVD. In the longitudinal analysis of correlations between baseline biological parameters and the follow-up calcification assessment using radiographs we found LDL-cholesterol, HDL/LDL, and the ApoB/ApoA ratio significantly associated with the MACD (P< 0.01). In a subset of patients presenting with calcification at both baseline and at follow-up, all cholesterol levels were significantly associated with the MACD (P< 0.01) index. AC24 index was not correlated with blood parameters.</p> <p>Conclusion</p> <p>Patterns of calcification identified by the MACD, but not the AC24 index, appear to contain useful biological information perhaps explaining part of the improved identification of risk of cardiovascular death of the MACD index. Correlations of MACD but not the AC24 with glucose levels at baseline suggest that hyperglycemia may contribute to unique patterns of calcification indicated by the MACD.</p

Human macrophage foam cells degrade atherosclerotic plaques through cathepsin K mediated processes

<p>Abstract</p> <p>Background</p> <p>Proteolytic degradation of Type I Collagen by proteases may play an important role in remodeling of atherosclerotic plaques, contributing to increased risk of plaque rupture.</p> <p>The aim of the current study was to investigate whether human macrophage foam cells degrade the extracellular matrix (ECM) of atherosclerotic plaques by cathepsin K mediated processes.</p> <p>Methods</p> <p>We 1) cultured human macrophages on ECM and measured cathepsin K generated fragments of type I collagen (C-terminal fragments of Type I collagen (CTX-I) 2) investigated the presence of CTX-I in human coronary arteries and 3) finally investigated the clinical potential by measuring circulating CTX-I in women with and without radiographic evidence of aortic calcified atherosclerosis.</p> <p>Results</p> <p>Immune-histochemistry of early and advanced lesions of coronary arteries demonstrated co-localization of Cathepsin-K and CTX-I in areas of intimal hyperplasia and in shoulder regions of advanced plaques. Treatment of human monocytes with M-CSF or M-CSF+LDL generated macrophages and foam cells producing CTX-I when cultured on type I collagen enriched matrix. Circulating levels of CTX-I were not significantly different in women with aortic calcifications compared to those without.</p> <p>Conclusions</p> <p>Human macrophage foam cells degrade the atherosclerotic plaques though cathepsin K mediated processes, resulting in increase in levels of CTX-I. Serum CTX-I was not elevated in women with aortic calcification, likely due to the contribution of CTX-I from osteoclastic bone resorption which involves Cathepsin-K. The human macrophage model system may be used to identify important pathway leading to excessive proteolytic plaque remodeling and plaque rupture.</p