Endothelial cells and cathepsins: Biochemical and biomechanical regulation

Abstract

Cathepsins are mechanosensitive proteases that are regulated not only by biochemical factors, but are also responsive to biomechanical forces in the cardiovascular system that regulate their expression and activity to participate in cardiovascular tissue remodeling. Their elastinolytic and collagenolytic activity have been implicated in atherosclerosis, abdominal aortic aneurysms, and in heart valve disease, all of which are lined by endothelial cells that are the mechanosensitive monolayer of cells that sense and respond to fluid shear stress as the blood flows across the surfaces of the arteries and valve leaflets. Inflammatory cytokine signaling is integrated with biomechanical signaling pathways by the endothelial cells to transcribe, translate, and activate either the cysteine cathepsins to remodel the tissue or to express their inhibitors to maintain healthy cardiovascular tissue structure. Other cardiovascular diseases should now be included in the study of the cysteine cathepsin activation because of the additional biochemical cues they provide that merges with the already existing hemodynamics driving cardiovascular disease. Sickle cell disease causes a chronic inflammation including elevated TNFα and increased numbers of circulating monocytes that alter the biochemical stimulation while the more viscous red blood cells due to the sickling of hemoglobin alters the hemodynamics and is associated with accelerated elastin remodeling causing pediatric strokes. HIV-mediated cardiovascular disease also occurs earlier in than the broader population and the influence of HIV-proteins and antiretrovirals on endothelial cells must be considered to understand these accelerated mechanisms in order to identify new therapeutic targets for prevention.

Impaired endothelial shear stress induces podosome assemblyviaVEGF up‐regulation

“…Similarly, activity and expression of cathepsins was enhanced in aortic valves and in endothelial cells in the absence of shear stress (15, 36, 37). Moreover, the activities of MMPs and cathepsins increased in atherosclerotic lesions exposed to low or oscillatory flow in vivo (15, 33, 38). Of note, very high shear stress may likewise provoke proteolytic processes.…”

“…Shear stress as an important stimulus for vascular remodeling processes is known to alter protease release and activity in the vasculature (15, 16). To date, it remains unknown whether podosomes are involved in the shear stress‐induced alterations of protease release and activity; thus, we studied endothelial podosome formation and accompanied local protease activity under various flow conditions and we identified signaling pathways that induce podosome‐dependent matrix degradation.…”

l‐Homocysteine‐induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia

“…It is well recognized that vascular inflammation is the basis for the development of cardiovascular diseases (Libby, ). Furthermore, it has been demonstrated that Hcy‐induced vascular inflammation is an important player in the pathophysiology of hyperhomocysteinaemia‐associated hypertension and atherosclerosis (Familtseva et al ., ; Platt and Shockey, ). However, it was not clear which factors are responsible for vascular inflammation in hyperhomocysteinaemia.…”

“…Cathepsins are lysosomal cysteine proteases and belong to the papain family of proteases that is composed of 11 members, while endothelial cells mainly express cathepsins K, B, S, L and V (Platt and Shockey, ). It has reported that human cathepsin V, but not human cathepsin L, is the analogue of mouse cathepsin L (Yasuda et al ., ).…”

“…Cathepsins are lysosomal cysteine proteases and belong to the papain family of proteases that comprises 11 members, while endothelial cells mainly express cathepsin K, B, S, L and V (Reichenbach et al ., ; Platt and Shockey, ). The elastolytic and collagenolytic activities of cathepsins are involved in vascular remodelling and inflammation (Du et al ., ).…”