TY - JOUR
T1 - The inflammatory profile of cteph‐derived endothelial cells is a possible driver of disease progression
AU - Smolders, Valérie F.E.D.
AU - Lodder, Kirsten
AU - Rodríguez, Cristina
AU - Tura‐ceide, Olga
AU - Barberà, Joan Albert
AU - Wouter Jukema, J.
AU - Quax, Paul H.A.
AU - Goumans, Marie José
AU - Kurakula, Kondababu
N1 - Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/4
Y1 - 2021/4
N2 - Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension characterized by the presence of fibrotic intraluminal thrombi and causing obliteration of the pulmonary arteries. Although both endothelial cell (EC) dysfunction and inflammation are linked to CTEPH pathogenesis, regulation of the basal inflammatory response of ECs in CTEPH is not fully understood. Therefore, in the present study, we investigated the role of the nuclear factor (NF)‐κB pro‐inflammatory signaling pathway in ECs in CTEPH under basal conditions. Basal mRNA levels of interleukin (IL)‐8, IL‐1β, monocyte chemoattractant protein‐1 (MCP‐1), C‐C motif chemokine ligand 5 (CCL5), and vascular cell adhesion molecule‐1 (VCAM‐1) were upregulated in CTEPH‐ECs compared to the control cells. To assess the involvement of NF‐κB signaling in basal inflammatory activation, CTEPH‐ECs were incubated with the NF‐κB inhibitor Bay 11‐7085. The increase in pro‐inflammatory cytokines was abolished when cells were incubated with the NF‐κB inhibitor. To determine if NF‐κB was indeed activated, we stained pulmonary endarterectomy (PEA) specimens from CTEPH patients and ECs isolated from PEA specimens for phospho‐NF‐κB‐ P65 and found that especially the vessels within the thrombus and CTEPH‐ECs are positive for phospho‐NF‐κB‐P65. In summary, we show that CTEPH‐ECs have a pro‐inflammatory status under basal conditions, and blocking NF‐κB signaling reduces the production of inflammatory factors in CTEPH‐ECs. Therefore, our results show that the increased basal pro‐inflammatory status of CTEPH‐ECs is, at least partially, regulated through activation of NF‐κB signaling and potentially contributes to the pathophysiology and progression of CTEPH.
AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension characterized by the presence of fibrotic intraluminal thrombi and causing obliteration of the pulmonary arteries. Although both endothelial cell (EC) dysfunction and inflammation are linked to CTEPH pathogenesis, regulation of the basal inflammatory response of ECs in CTEPH is not fully understood. Therefore, in the present study, we investigated the role of the nuclear factor (NF)‐κB pro‐inflammatory signaling pathway in ECs in CTEPH under basal conditions. Basal mRNA levels of interleukin (IL)‐8, IL‐1β, monocyte chemoattractant protein‐1 (MCP‐1), C‐C motif chemokine ligand 5 (CCL5), and vascular cell adhesion molecule‐1 (VCAM‐1) were upregulated in CTEPH‐ECs compared to the control cells. To assess the involvement of NF‐κB signaling in basal inflammatory activation, CTEPH‐ECs were incubated with the NF‐κB inhibitor Bay 11‐7085. The increase in pro‐inflammatory cytokines was abolished when cells were incubated with the NF‐κB inhibitor. To determine if NF‐κB was indeed activated, we stained pulmonary endarterectomy (PEA) specimens from CTEPH patients and ECs isolated from PEA specimens for phospho‐NF‐κB‐ P65 and found that especially the vessels within the thrombus and CTEPH‐ECs are positive for phospho‐NF‐κB‐P65. In summary, we show that CTEPH‐ECs have a pro‐inflammatory status under basal conditions, and blocking NF‐κB signaling reduces the production of inflammatory factors in CTEPH‐ECs. Therefore, our results show that the increased basal pro‐inflammatory status of CTEPH‐ECs is, at least partially, regulated through activation of NF‐κB signaling and potentially contributes to the pathophysiology and progression of CTEPH.
KW - Chronic thromboembolic pulmonary hypertension
KW - Endothelial dysfunction
KW - Inflammation
KW - Nuclear factor‐κB sig-naling
UR - http://www.scopus.com/inward/record.url?scp=85103863327&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells10040737
DO - https://doi.org/10.3390/cells10040737
M3 - Article
C2 - 33810533
SN - 2073-4409
VL - 10
JO - Cells
JF - Cells
IS - 4
M1 - 737
ER -