RESUMEN
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.
Asunto(s)
Células Endoteliales/patología , Proteínas HSP70 de Choque Térmico/metabolismo , Hipertensión Pulmonar/patología , Arteria Pulmonar/patología , Estrés Mecánico , Tromboembolia/complicaciones , Regulación hacia Arriba , Fenómenos Biomecánicos , Enfermedad Crónica , Chaperón BiP del Retículo Endoplásmico , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/metabolismo , Resistencia al CorteRESUMEN
Hipertensão pulmonar crônica tromboembólica é observada em até 3,8 por cento dos pacientes que sobreviveram a embolia pulmonar aguda. O desenvolvimento da técnica da tromboendarterectomia possibilitou a melhora significativa da sobrevida dos pacientes portadores de hipertensão pulmonar tromboembólica, com resolução do quadro hipertensivo na maioria dos pacientes operados. Nos últimos anos, tornou-se possível a definição de critérios mais claros para a indicação cirúrgica, assim como de marcadores de prognóstico, o que determinou significativa diminuição do risco cirúrgico associado ao procedimento. Atualmente tratamento médico com drogas está sendo feito em pacientes em que a tromboendarterectomia não apresentou bons resultados ou foi contra-indicada.