Cathepsin G activity lowers plasma LDL and reduces atherosclerosis

Abstract

Cathepsin G (CatG), a serine protease present in mast cells and neutrophils, can produce angiotensin-II (Ang-II) and degrade elastin. Here we demonstrate increased CatG expression in smooth muscle cells (SMCs), endothelial cells (ECs), macrophages, and T cells from human atherosclerotic lesions. In low-density lipoprotein (LDL) receptor-deficient (Ldlr−/−) mice, the absence of CatG reduces arterial wall elastin degradation and attenuates early atherosclerosis when mice consume a Western diet for 3 months. When mice consume this diet for 6 months, however, CatG deficiency exacerbates atherosclerosis in aortic arch without affecting lesion inflammatory cell content or extracellular matrix accumulation, but raises plasma total cholesterol and LDL levels without affecting high-density lipoprotein (HDL) or triglyceride levels. Patients with atherosclerosis also have significantly reduced plasma CatG levels that correlate inversely with total cholesterol (r= −0.535, P<0.0001) and LDL cholesterol (r= −0.559, P<0.0001), but not with HDL cholesterol (P=0.901) or triglycerides (P=0.186). Such inverse correlations with total cholesterol (r= −0.504, P<0.0001) and LDL cholesterol (r= −0.502, P<0.0001) remain significant after adjusting for lipid lowering treatments among this patient population. Human CatG degrades purified human LDL, but not HDL. This study suggests that CatG promotes early atherogenesis through its elastinolytic activity, but suppresses late progression of atherosclerosis by degrading LDL without affecting HDL or triglycerides.

Systemic mastocytosis associates with cardiovascular events despite lower plasma lipid levels

“…Recently, it was established that chymase cleaves ApoA-I resulting in loss of its anti-inflammatory functions [20]. Moreover, cathepsin G, another protease released from mast cells, has been reported to degrade LDL, reducing LDL-C and ApoB levels [21]. Excessive mast cell protease activity in SM patients may be, at least in part, responsible for the altered apolipoprotein profile observed.…”

Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment

“…30–32 Although little contribution of CatG has been described in the microcirculation in terms of leukocyte recruitment, several studies have pointed toward its potential importance in inflammation in large vessels. 33–35 This could denote a tissue-specific relevance of these proteases, where CatG assists myeloid cells to adhere to inflamed arteries, whereas neutrophil elastase controls microvascular recruitment. Interestingly, we found that the effect of CatG is independent of its proteolytic activity, but could be abrogated with an antibody.…”

Mast cell derived carboxypeptidase A3 is decreased among patients with advanced coronary artery disease

“…However, MC are not the only source of the enzyme, it is also released from activated neutrophils and macrophages [8][9][10]. Despite that cathepsin G may promote early atherogenesis as it is an elastase [11] and collagenase activator [12], Wang et al [13] suggested that cathepsin G promotes early atherogenesis through its elastinolytic activity, but at the same time suppresses late progression of atherosclerosis. In their study, patients with atherosclerosis had significantly reduced plasma levels of cathepsin G that were in negative correlation with total cholesterol and low density lipoprotein (LDL), but not high density lipoprotein (HDL) or triglycerides, suggesting a role of cathepsin G in degradation of LDL without affecting HDL or triglycerides [13].…”