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

Abstract

BackgroundProteolytic degradation of Type I Collagen by proteases may play an important role in remodeling of atherosclerotic plaques, contributing to increased risk of plaque rupture.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.MethodsWe 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.ResultsImmune-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.ConclusionsHuman 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.

Role of Cathepsin K, L and S in Blood Vessel Remodeling

“…The destructive role of cathepsin K in macrophage foam cells was confirmed by immunohistochemical analysis that revealed accumulation of collagen type I degradation products close to cathepsin K immunoreactivity. These results were supported by an in vitro experiment where incubation of human macrophage foam cells on a collagen matrix resulted in the accumulation of collagen degradation products (Barascuk et al, 2010). Cathepsin K expression in endothelial cells in human atherosclerotic plaques also correlated with internal elastic lamina destruction (Platt et al, 2007).…”

Type I collagen degradation during tissue repair: Comparison of mechanisms following fracture and acute coronary syndromes

“…It has been demonstrated that foam cells, a pathological finding in lipid-rich atherosclerotic plaques, are able to produce active cathepsin K and release CTX [5]. Collagen turnover in the caps of vulnerable plaques has been implicated in their propensity to rupture [17], leading to myocardial infarction.…”

“…The role of cathepsins in the heart is emerging. It has been demonstrated that foam cells in atherosclerotic plaques within the cardiac vasculature are capable of producing active cathepsin K [5].…”

“…More recently, cathepsin K and its breakdown product CTX have been identified in advanced atherosclerotic plaques [5]. The observation of cardiomyopathy-type changes in cathepsin L −/− mice and the demonstration of this enzyme's ability to cleave CTX [4] further prompted our interest into this potential mechanism.…”

Improving management of STEMI patients treated with primary PCI: Pharmacotherapy, renal function estimation and gender perspective

“…An imbalance between cystatin C and cathepsins may trigger a pathophysiological cascade leading to atherosclerosis 214 and collagen degradation in the cap of the atherosclerotic plaque, increasing the risk of rupture. 215,216 Levels of cathepsins are elevated in STEMI patients at arrival. 217 Additionally, cathepsins are probably involved in healing process after STEMI and cathepsin-mediated turnover of collagen is increased during the first days following the myocardial infarction.…”