PMID- 33810533 OWN - NLM STAT- MEDLINE DCOM- 20211019 LR - 20211019 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 10 IP - 4 DP - 2021 Mar 26 TI - The Inflammatory Profile of CTEPH-Derived Endothelial Cells Is a Possible Driver of Disease Progression. LID - 10.3390/cells10040737 [doi] LID - 737 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)-kappaB pro-inflammatory signaling pathway in ECs in CTEPH under basal conditions. Basal mRNA levels of interleukin (IL)-8, IL-1beta, 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-kappaB signaling in basal inflammatory activation, CTEPH-ECs were incubated with the NF-kappaB inhibitor Bay 11-7085. The increase in pro-inflammatory cytokines was abolished when cells were incubated with the NF-kappaB inhibitor. To determine if NF-kappaB was indeed activated, we stained pulmonary endarterectomy (PEA) specimens from CTEPH patients and ECs isolated from PEA specimens for phospho-NF-kappaB-P65 and found that especially the vessels within the thrombus and CTEPH-ECs are positive for phospho-NF-kappaB-P65. In summary, we show that CTEPH-ECs have a pro-inflammatory status under basal conditions, and blocking NF-kappaB 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-kappaB signaling and potentially contributes to the pathophysiology and progression of CTEPH. FAU - Smolders, Valerie F E D AU - Smolders VFED AUID- ORCID: 0000-0002-9863-7581 AD - Department of Surgery, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. AD - Department of Cell and Chemical Biology, Laboratory for CardioVascular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. FAU - Lodder, Kirsten AU - Lodder K AD - Department of Cell and Chemical Biology, Laboratory for CardioVascular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. FAU - Rodriguez, Cristina AU - Rodriguez C AUID- ORCID: 0000-0003-0614-6214 AD - Department of Pulmonary Medicine, Hospital Clinic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain. AD - Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital de Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institut (IDIBGI), 17190 Girona, Spain. FAU - Tura-Ceide, Olga AU - Tura-Ceide O AD - Department of Pulmonary Medicine, Hospital Clinic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain. AD - Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital de Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institut (IDIBGI), 17190 Girona, Spain. AD - Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain. FAU - Barbera, Joan Albert AU - Barbera JA AD - Department of Pulmonary Medicine, Hospital Clinic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain. AD - Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain. FAU - Jukema, J Wouter AU - Jukema JW AD - Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. FAU - Quax, Paul H A AU - Quax PHA AUID- ORCID: 0000-0002-6853-5760 AD - Department of Surgery, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. FAU - Goumans, Marie Jose AU - Goumans MJ AUID- ORCID: 0000-0001-9344-6746 AD - Department of Cell and Chemical Biology, Laboratory for CardioVascular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. FAU - Kurakula, Kondababu AU - Kurakula K AUID- ORCID: 0000-0002-9830-6344 AD - Department of Cell and Chemical Biology, Laboratory for CardioVascular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. LA - eng GR - 675527/MOGLYNET H2020-MSCA-ITN-EJD grant/ GR - CP17/00114/Miguel Servet grant from the Instituto de Salud Carlos III/ GR - PI15/00582 and PI18/00960/Catalan Society of Pneumology (SOCAP 2019)/ GR - PHAEDRA-IMPACT/DCVA consortium grant PHAEDRA-IMPACT/ GR - 5.2.17.198J0/Dutch Lung Foundation/ GR - W18378-2-32/Leiden University Foundation grant/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210326 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (Transcription Factor RelA) SB - IM MH - *Disease Progression MH - Endarterectomy MH - Endothelial Cells/*pathology MH - Female MH - Fluorescence MH - Gene Expression Regulation MH - Hemodynamics MH - Humans MH - Hypertension, Pulmonary/*complications/genetics/*pathology/physiopathology MH - Inflammation/genetics/*pathology/physiopathology MH - Male MH - Middle Aged MH - Phosphorylation MH - Thromboembolism/*complications/genetics/*pathology/physiopathology MH - Transcription Factor RelA/antagonists & inhibitors/metabolism PMC - PMC8067175 OTO - NOTNLM OT - chronic thromboembolic pulmonary hypertension OT - endothelial dysfunction OT - inflammation OT - nuclear factor-kappaB signaling COIS- The authors declare no conflict of interest. EDAT- 2021/04/04 06:00 MHDA- 2021/10/21 06:00 PMCR- 2021/03/26 CRDT- 2021/04/03 01:36 PHST- 2020/11/18 00:00 [received] PHST- 2021/03/19 00:00 [revised] PHST- 2021/03/19 00:00 [accepted] PHST- 2021/04/03 01:36 [entrez] PHST- 2021/04/04 06:00 [pubmed] PHST- 2021/10/21 06:00 [medline] PHST- 2021/03/26 00:00 [pmc-release] AID - cells10040737 [pii] AID - cells-10-00737 [pii] AID - 10.3390/cells10040737 [doi] PST - epublish SO - Cells. 2021 Mar 26;10(4):737. doi: 10.3390/cells10040737.