Shear stress-exposed pulmonary artery endothelial cells fail to upregulate HSP70 in chronic thromboembolic pulmonary hypertension.

Autor: Salibe-Filho W; Pulmonary Division, Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - São Paulo, Brazil., Araujo TLS; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil., G Melo E; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil., B C T Coimbra L; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil., Lapa MS; Pulmonary Division, Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - São Paulo, Brazil., Acencio MMP; Pulmonary Division, Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - São Paulo, Brazil., Freitas-Filho O; Cardiovascular Surgery Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - São Paulo, Brazil., Capelozzi VL; Department of Pathology, Faculdade de Medicina da Universidade de São Paulo - São Paulo, Brazil., Teixeira LR; Pulmonary Division, Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - São Paulo, Brazil., Fernandes CJCS; Pulmonary Division, Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - São Paulo, Brazil., Jatene FB; Cardiovascular Surgery Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - São Paulo, Brazil., Laurindo FRM; Vascular Biology Laboratory, Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - São Paulo, Brazil., Terra-Filho M; Pulmonary Division, Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - São Paulo, Brazil.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2020 Dec 03; Vol. 15 (12), pp. e0242960. Date of Electronic Publication: 2020 Dec 03 (Print Publication: 2020).
DOI: 10.1371/journal.pone.0242960
Abstrakt: The pathophysiological mechanisms underlying chronic thromboembolic pulmonary hypertension (CTEPH) are still unclear. Endothelial cell (EC) remodeling is believed to contribute to this pulmonary disease triggered by thrombus and hemodynamic forces disbalance. Recently, we showed that HSP70 levels decrease by proatherogenic shear stress. Molecular chaperones play a major role in proteostasis in neurological, cancer and inflammatory/ infectious diseases. To shed light on microvascular responses in CTEPH, we characterized the expression of molecular chaperones and annexin A2, a component of the fibrinolytic system. There is no animal model that reproduces microvascular changes in CTEPH, and this fact led us to isolated endothelial cells from patients with CTEPH undergoing pulmonary endarterectomy (PEA). We exposed CTEPH-EC and control human pulmonary endothelial cells (HPAEC) to high- (15 dynes/cm2) or low- (5 dynes/cm2) shear stress. After high-magnitude shear stress HPAEC upregulated heat shock protein 70kDa (HSP70) and the HSP ER paralogs 78 and 94kDa glucose-regulated protein (GRP78 and 94), whereas CTEPH-ECs failed to exhibit this response. At static conditions, both HSP70 and HSP90 families in CTEPH-EC are decreased. Importantly, immunohistochemistry analysis showed that HSP70 expression was downregulated in vivo, and annexin A2 was upregulated. Interestingly, wound healing and angiogenesis assays revealed that HSP70 inhibition with VER-155008 further impaired CTEPH-EC migratory responses. These results implicate HSP70 as a novel master regulator of endothelial dysfunction in type 4 PH. Overall, we first show that global failure of HSP upregulation is a hallmark of CTEPH pathogenesis and propose HSP70 as a potential biomarker of this condition.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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