The pathophysiology of endothelial cells isolated from patients with hypertensive pulmonary thromboembolism: mechanisms regulated by HSP70

• Grant number: 20/11249-3
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): September 01, 2020
• Effective date (End): February 28, 2023
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Thaís Larissa Araujo de Oliveira Silva
• Grantee: Luiza Bitencourt de Carvalho Terci Coimbra
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/13739-8 - Molecular chaperone HSP70 mediates proteostasis in endothelial cells response to hemodynamic force, AP.JP

Abstract

Chronic thromboembolic pulmonary hypertension (TEPH) is characterized by the formation of intraluminal thrombus leading to right ventricular overload. It is characterized by the presence of anticardiolipin antibodies, factor VIII, macrophage chemo-attracting protein, endothelin-1 and low levels of thromobomodulin [1]. The first line of treatment is anticoagulation and endarterectomy (PEA) in eligible patients, with the last leading to a good prognosis [2]. However, about 35% of patients have persistent pulmonary hypertension after PEA [3]. Endothelial dysfunction, vascular remodeling, high magnitude shear stress [4] and hypoxia [5] contribute to the pathogenesis of the disease. However, the molecular mechanisms remain to be elucidated, with vascular endothelial growth factor receptor 2 (VEGFR2) [6], adhesion molecule 1 of endothelial cell platelet (PECAM-1) [7] and reduced mRNA of autophagy markers [ 8]. In an attempt to understand the pathogenesis of the disease, we isolated endothelial cells (ECL) from TEPH patients undergoing PEA. We identified a failure in proteostasis in ECL with reduced expression of the molecular chaperones of members of the HSP90 and HSP70 family more reduced by high magnitude shear stress. It is important to highlight the reduction of HSP70 in the tissue of patients, indicating that ECLs maintain a phenotype found in the vessel and serve as a good model to study the mechanisms associated with TEPH. Our hypothesis is that HSP70 has a protective role in TEPH and its loss of function would lead to ECL dysfunction. We will investigate the sensitivity to cell death, the total protein synthesis of ECLs subjected to high magnitude shear stress. We will analyze whether the restoration of HSP70 levels promotes migration and angiogenic properties of ECL. In addition, our recent data on the interaction of thrombomodulin with HSP70 leads us to investigate whether the low expression of HSP70 would be responsible for reducing the expression of thrombomodulin in patients with TEPH. This project will be carried out with the support of the MD researcher. William Salibe. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SALIBE-FILHO, WILLIAM; ARAUJO, THAIS L. S.; MELO, EVERTON G.; COIMBRA, LUIZA B. C. T.; LAPA, MONICA S.; ACENCIO, MILENA M. P.; FREITAS-FILHO, ORIVAL; CAPELOZZI, VERA LUIZA; TEIXEIRA, LISETE RIBEIRO; FERNANDES, CAIO J. C. S.; et al. Shear stress-exposed pulmonary artery endothelial cells fail to upregulate HSP70 in chronic thromboembolic pulmonary hypertension. PLoS One, v. 15, n. 12, DEC 3 2020. (20/11249-3, 19/20435-8, 15/06210-2, 18/13739-8, 13/07937-8)