Research Article: Sickle Cell Disease Activates Peripheral Blood Mononuclear Cells to Induce Cathepsins K and V Activity in Endothelial Cells

Date Published: April 9, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Philip M. Keegan, Sindhuja Surapaneni, Manu O. Platt.


Sickle cell disease is a genetic disease that increases systemic inflammation as well as the risk of pediatric strokes, but links between sickle-induced inflammation and arterial remodeling are not clear. Cathepsins are powerful elastases and collagenases secreted by endothelial cells and monocyte-derived macrophages in atherosclerosis, but their involvement in sickle cell disease has not been studied. Here, we investigated how tumor necrosis alpha (TNFα) and circulating mononuclear cell adhesion to human aortic endothelial cells (ECs) increase active cathepsins K and V as a model of inflammation occurring in the arterial wall. ECs were stimulated with TNFα and cultured with peripheral blood mononuclear cells (PBMCs) from persons homozygous for sickle (SS) or normal (AA) hemoglobin. TNFα was necessary to induce cathepsin K activity, but either PBMC binding or TNFα increased cathepsin V activity. SS PBMCs were unique; they induced cathepsin K in ECs without exogenous TNFα (n = 4, P < 0.05). Inhibition of c-Jun N-terminal kinase (JNK) significantly reduced cathepsins K and V activation by 60% and 51%, respectively. Together, the inflammation and activated circulating mononuclear cells upregulate cathepsin activity through JNK signaling, identifying new pharmaceutical targets to block the accelerated pathology observed in arteries of children with sickle cell disease.

Partial Text

Sickle cell disease is a genetic disorder that causes in vivo polymerization of hemoglobin molecules into rigid fibers within red blood cells, deforming them in the canonically described “sickle” shape. Rigid, sickled red blood cells and the byproducts of their hemolysis cause chronic vascular damage and increase systemic levels of inflammatory cytokines, mobilized mononuclear cells [1], and pathological levels of increased monocyte adhesion to the endothelium [2, 3]. Overall, these pathological inflammatory conditions and mononuclear cell-endothelial cell interactions may contribute to intimal thickening, and lumen narrowing seen in pulmonary hypertension and stroke lesions of children; pulmonary hypertension is responsible for 20–30% of sickle-cell-related deaths in adult patients [4, 5] and 11% of children with sickle cell disease will suffer from a major stroke by the age of 16.

Endothelial cell expression of cathepsins and increased cathepsin-mediated elastase activity are upregulated during atherosclerotic development and induced by inflammation and altered hemodynamics [9, 12, 13, 26, 27], which are both present in sickle cell disease [26], leading to our hypothesis that elevated TNFα and increased circulating mononuclear cells would stimulate increased endothelial cell cathepsin activity. This elevated activity may contribute to arterial remodeling in sickle cell disease. The findings of this study specifically implicate TNFα and mononuclear cell binding to endothelium as key mediators, and that circulating mononuclear cells in sickle cell disease are predisposed to induce cathepsin proteolytic activity.

Elevated inflammatory factors and circulating mononuclear cells inherent to sickle cell disease induce pathologically high levels of cathepsins K and V activity when binding to and stimulating endothelial cells, increasing proteolytic activity that may be involved in arterial wall remodeling to increase risk of stroke and pulmonary hypertension. There is a pressing need for novel pharmaceutical targets to inhibit these activities, and from this work, we propose that JNK, cathepsin K, and cathepsin V are three new targets for inhibition to reduce pathological arterial remodeling in sickle cell disease.