NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

Abstract

Wynants M, Vengethasamy L, Ronisz A, Meyns B, Delcroix M, Quarck R. NF-B pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 305: L934-L942, 2013. First published October 4, 2013 doi:10.1152/ajplung.00034.2013.-Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of proximal pulmonary arteries. The cellular and molecular mechanisms underlying the pathogenesis remain incompletely understood, although we recently evidenced the potential involvement of the inflammatory marker C-reactive protein (CRP). We aimed to investigate the intracellular mechanisms induced by CRP in proximal pulmonary arterial endothelial cells (PAEC). PAEC were isolated from vascular material obtained during pulmonary endarterectomy. RNA was extracted from CRP-stimulated PAEC, and first-stand cDNA was generated. A RT 2 profiler PCR Array was used to evaluate the expression of 84 key genes related to NF-B-mediated signal transduction. CRP-induced NF-B activation was studied. The effects of pyrrolidine-dithio-carbamate ammonium (PDTC), an inhibitor of the NF-B pathway, were investigated on CRP-induced adhesion of monocytes to PAEC, adhesion molecule expression, endothelin-1 (ET-1), interleukin-6 (IL-6), and von Willebrand factor (vWF) secretion. Compared with nonstimulated PAEC, serotonin receptor 2B was downregulated by 25%, inhibitor of NF-B kinase subunit epsilon (IKBKE) by 30%, and toll-like receptor-4 and -6 by 18 and 39%, respectively, in CRP-stimulated PAEC. The transcription factor FOS was threefold upregulated. CRP induced RelA/NF-Bp65 phosphorylation. PDTC dose dependently inhibited the adhesion of monocytes to CRP-stimulated PAEC. PDTC also inhibited the CRP-induced expression of ICAM-1 at the surface of PAEC. PDTC impaired the secretion of ET-1 by 18% and tended to inhibit the secretion of IL-6 by CRP-stimulated PAEC by 46%. PDTC did not inhibit the CRP-induced secretion of vWF. These results suggest an involvement of the NF-B pathway in mediating different effects of CRP on proximal CTEPH-PAEC. C-reactive protein; endothelial cells; NF-B; chronic thromboembolic pulmonary hypertension CHRONIC THROMBOEMBOLIC PULMONARY hypertension (CTEPH) is a severe cause of pulmonary hypertension characterized by an obliteration of proximal pulmonary arteries by intraluminal thrombi and fibrous stenosis. Pulmonary embolism, either as single or recurrent episodes, is thought to be the initiating event followed by progressive pulmonary vascular remodeling. Vascular disobliteration by pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients (38).Knowledge of the physiopathology of CTEPH remains incomplete. Proximal lesions share similarities with atherosclerotic plaques, including media thickening and neointima formation (1). Risk factors for CTEPH include size of the initial thrombus, elevated factor VIII, circulating phospholipid antibodies, and fibrinogen intrinsic ...

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

“…Recently, the NF-κB signaling pathway was found to play a role in oxidative stress in human and experimental PAH [29], [30]. Incubation of HPASMCs with 4-HNE promoted phosphorylation and degradation of the NF-κB inhibitor IκBα, as well as phosphorylated NF-κB p65 in the cytoplasm (Fig.…”

Contribution of inflammation and impaired angiogenesis to the pathobiology of chronic thromboembolic pulmonary hypertension

“…Elevated circulating biomarkers of tissue remodelling, such as matrix metalloproteinases (MMPs) [15], and disordered angiogenesis, mainly characterised by impaired vascular endothelial growth factor (VEGF) expression [16] have also been observed in pulmonary hypertension. This inflammatory concept is further supported by our recent observations that CTEPH patients display elevated circulating C-reactive protein (CRP) levels, which decrease significantly after PEA [17], and that CRP may increase endothelium dysfunction and the proliferating capacities of endothelial and smooth muscle cells isolated from PEA material [18,19].…”

C-reactive protein stimulates RAGE expression in human coronary artery endothelial cells in vitro via ROS generation and ERK/NF-κB activation

“…To examine whether NF-κB signaling pathway is involved in CRP-induced RAGE expression, HCAECs were pretreated with the NF-κB inhibitor (PDTC, 100 μmol/L) for one hour followed by CRP (50 μg/mL) treatment for six hours (for detecting NF-κB phosphorylation and translocation) or twelve hours (for detecting RAGE & β-actin expression) [12,18] . NF-κB activation was demonstrated by detecting nuclear translocation and the phosphorylation of NF-κB p65.…”