Cathepsin G deficiency decreases complexity of atherosclerotic lesions in apolipoprotein E-deficient mice

Abstract

Rafatian N, Karunakaran D, Rayner KJ, Leenen FH, Milne RW, Whitman SC. Cathepsin G deficiency decreases complexity of atherosclerotic lesions in apolipoprotein E-deficient mice.

Cathepsin G activity lowers plasma LDL and reduces atherosclerosis

“…CatG may either promote apoptosis [34, 35], or inhibit this process via Ang-II production [36]. Prior study from CatG-insufficient Apoe −/− Ctsg +/− mice demonstrated reduced apoptosis in atherosclerotic lesions [21]. However, TUNEL staining showed increased apoptosis in atherosclerotic lesions from Ldlr −/− Ctsg −/− mice at both the 3- and 6-month time points (Fig.…”

“…The mechanistic studies presented here disclose a heretofore unrecognized role for CatG in the regulation of plasma total and LDL cholesterol levels directly by degrading apoB on LDL (while not affecting HDL), although our study did not prove a role of CatG activity in Ang-II production in systolic or diastolic blood pressure changes during atherogenesis. A recent study using Apoe −/− Ctsg +/+ and CatG-haploinsufficient Apoe −/− Ctsg +/− mice suggested an insignificant contribution of CatG in atherosclerosis in these animals that accumulate primarily beta-VLDL rather than LDL [21]. CatG may behave differently depending on the type of hyperlipidemia, as does the cysteine protease cathepsin S (CatS) which we demonstrated significantly reduces atherosclerosis in CatS-deficient Ldlr −/− Ctss −/− mice [23], but not in Apoe −/− Ctss −/− mice (unpublished data) compared with corresponding CatS-sufficient control mice.…”

“…Increased CatG in aortas may degrade VE-cadherin and fibronectin, thereby enhancing the expression and activation of MMPs [13] and the interaction of blood-borne leukocytes with the luminal endothelium [20]. A recent study using Apoe −/− mice demonstrated that CatG insufficiency ( Apoe −/− Ctsg +/− ) significantly reduced lesion collagen and SMC content, and apoptotic cell number [21], supporting a role of CatG in experimental atherosclerosis.…”

The walking dead: macrophage inflammation and death in atherosclerosis

“…Defective efferocytosis can result from phagocyte oxidative stress (due to reduced cholesterol efflux post-apoptotic cell engulfment [70]) and/or the cleavage of MerTK receptors by ADAM17, inhibiting the ability of efferocytes to engulf apoptotic cells [71]. A number of studies have identified other key players Cathepsin G and ERK5, in regulating efficient efferocytosis in atherosclerotic mouse models and necrotic core regions [72,73]. Consistent with previous observations [65], we observed that necroptotic macrophages are efferocytosed less effectively compared to apoptotic cells [61] which suggests that this may contribute directly to necrotic debris accumulaion in the plaque.…”

Proteases in cardiometabolic diseases: Pathophysiology, molecular mechanisms and clinical applications

“…Cathepsin L has been shown to be the major contributor to apoptosis of the macrophages resulting in necrotic core formation, leading to atherosclerotic plaque instability [195]. Interestingly, one recent study showed that cathepsin G deficiency attenuated the complexity of atherosclerotic lesions in apolipoprotein E-deficient mice via dampening apoptosis [196]. Cathepsin S, on the other hand, improves fibrous cap stabilization, and helps monocyte adhesion and migration in an in vitro system [197].…”