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Pulmonary endothelial cells play a key role in the pathogenesis of Chronic Thromboembolic Pulmonary Hypertension (CTEPH). Increased synthesis and/or the release of intercellular adhesion molecule-1 (ICAM-1) by pulmonary endothelial cells of patients with CTEPH has been recently reported, suggesting a potential role for ICAM-1 in CTEPH. We studied pulmonary endarterectomy specimens from 172 patients with CTEPH and pulmonary artery specimens from 97 controls undergoing lobectomy for low-stage cancer without metastasis. ICAM-1 was overexpressed in vitro in isolated and cultured endothelial cells from endarterectomy specimens. Endothelial cell growth and apoptosis resistance were significantly higher in CTEPH specimens than in the controls (p < 0.001). Both abnormalities were abolished by pharmacological inhibition of ICAM-1 synthesis or activity. The overexpression of ICAM-1 contributed to the acquisition and maintenance of abnormal EC growth and apoptosis resistance via the phosphorylation of SRC, p38 and ERK1/2 and the overproduction of survivin. Regarding the ICAM-1 E469K polymorphism, the KE heterozygote genotype was significantly more frequent in CTEPH than in the controls, but it was not associated with disease severity among patients with CTEPH. ICAM-1 contributes to maintaining the abnormal endothelial cell phenotype in CTEPH. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary arterial hypertension (iPAH) is characterized by obstructive hyperproliferation and apoptosis resistance of distal pulmonary artery smooth muscle cells (PASMCs). T-type Ca 2 + channel blockers have been shown to reduce experimental pulmonary hypertension, although the impact of T-type channel inhibition remains unexplored in PASMCs from iPAH patients. Here we show that T-type channels Cav3.1 and Cav3.2 are present in the lung and PASMCs from iPAH patients and control subjects. The blockade of T-type channels by the specific blocker, TTA-A2, prevents cell cycle progression and PASMCs growth. In iPAH cells, T-type channel signaling fails to activate phosphatase PP2A, leading to an increase in ERK1/2, P38 activation. Moreover, T-type channel signaling is redirected towards the activation of the kinase Akt1, leading to increased expression of the anti-apoptotic protein survivin, and a decrease in the pro-apoptotic mediator FoxO3A. Finally, in iPAH cells, Akt1 is no longer able to regulate caspase 9 activation, whereas T-type channel overexpression reverses PP2A defect in iPAH cells but reinforces the deleterious effects of Akt1 activation. Altogether, these data highlight T-type channel signaling as a strong trigger of the pathological phenotype of PASMCs from iPAH patients (hyper-proliferation/cells survival and apoptosis resistance), suggesting that both T-type channels and PP2A may be promising therapeutic targets for pulmonary hypertension. [ABSTRACT FROM AUTHOR]

No prior proteomic screening study has centred on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.Plasma proteomic profiling was performed using multiplex immunoassay in 121 (discovery cohort) and 76 (validation cohort) PAH patients. The association between proteomic markers and RHMP, defined by the Mayo right heart score (combining RV strain, New York Heart Association (NYHA) class and N-terminal pro-brain natriuretic peptide (NT-proBNP)) and Stanford score (RV end-systolic remodelling index, NYHA class and NT-proBNP), was assessed by partial least squares regression. Biomarker expression was measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice.High levels of hepatocyte growth factor (HGF), stem cell growth factor-β, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk of heart failure who warrant closer follow-up and intensified therapy., Competing Interests: Conflict of interest: M. Amsallem has received a 2016 Young Investigator Seed Grant from the Vera Moulton Wall Center at Stanford, a 2019–2020 Stanford Maternal and Child Health Research Institute research seed grant, a research grant from Actelion-Janssen and speaker fees from Bayer. Conflict of interest: A.J. Sweatt has nothing to disclose. Conflict of interest: J. Arthur Ataam has nothing to disclose. Conflict of interest: J. Guihaire has nothing to disclose. Conflict of interest: F. Lecerf has nothing to disclose. Conflict of interest: M. Lambert has nothing to disclose. Conflict of interest: M.R. Ghigna has nothing to disclose. Conflict of interest: M.K. Ali has nothing to disclose. Conflict of interest: Y. Mao has nothing to disclose. Conflict of interest: E. Fadel has nothing to disclose. Conflict of interest: M. Rabinovitch has nothing to disclose. Conflict of interest: V. de Jesus Perez has nothing to disclose. Conflict of interest: E. Spiekerkoetter is funded by Stanford Cardiovascular Institute, National Heart Lung Blood Institute (NHLBI) at the National Institute of Health (NIH) grant R01 HL128734 and Department of Defense grant PR161256. Conflict of interest: O. Mercier has been supported by a public grant overseen by the French National Research Agency as part of the second Investissement d'Avenir program (ANR-15-RHUS-0002). Conflict of interest: F. Haddad has received research grants from Actelion-Janssen and Philips. Conflict of interest: R.T. Zamanian has nothing to disclose., (Copyright ©ERS 2021.)