Reconciling paradigms of abnormal pulmonary blood flow and quasi-malignant cellular alterations in pulmonary arterial hypertension

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.

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“…Others have shown that low shear stress is beneficial in pulmonary arteries [8]. Our data corroborate this view.…”

Section: Plos Onesupporting

confidence: 92%

“…However, in CTEPH patients, shear stress may reach above 15 dynes/cm 2 , especially in the unobstructed areas disrupting normal vascular homeostasis. The PH is tightly associated with CTEPH pathogenesis triggered by vascular remodeling [8]. The vessel tonus is mediated by endothelial cells in line with smooth muscle cell phenotype changes.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Yet several metabolic processes beyond the Warburg effect are emerging as integral to PH development, and understanding those fundamental molecular links in both the pulmonary vessels and RV will be essential for improving the clinical management of this exceptionally complex disease. Particularly exciting future directions in this field include interrogations of the molecular interconnections of metabolism with pathogenic processes such as shear stress and flow [ 102 ] as well as innate immunity [ 18 ]. In that context, the rapid innovations in molecular imaging via MRI and PET coupled with the development of metabolic tracers could provide an opportunity to individualise diagnostic and prognostic technology for PH.…”

Section: Discussionmentioning

confidence: 99%

Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice

Chan

Rubin

2017

Eur Respir Rev

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Pulmonary hypertension (PH) is an often-fatal vascular disease of unclear molecular origins. The pulmonary vascular remodelling which occurs in PH is characterised by elevated vasomotor tone and a pro-proliferative state, ultimately leading to right ventricular dysfunction and heart failure. Guided in many respects by prior evidence from cancer biology, recent investigations have identified metabolic aberrations as crucial components of the disease process in both the pulmonary vessels and the right ventricle. Given the need for improved diagnostic and therapeutic options for PH, the development or repurposing of metabolic tracers and medications could provide an effective avenue for preventing or even reversing disease progression. In this review, we describe the metabolic mechanisms that are known to be dysregulated in PH; we explore the advancing diagnostic testing and imaging modalities that are being developed to improve diagnostic capability for this disease; and we discuss emerging drugs for PH which target these metabolic pathways.

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“…Diversas teorias foram descritas com o propósito de explicar a não resolução dos trombos: anticoagulação inadequada, alterações na fibrinólise, infecção por Staphylococcus aureus, alterações na molécula de adesão de células endoteliais de plaquetas 1(PECAM-1) e o redirecionamento de fluxos sanguíneos na circulação pulmonar (9)(10)(11)(12) . Dorfmüller et al (13) descreveram alteração das veias pulmonares, pelo remodelamento fibrótico reativo da parede (19) Foi demonstrado previamente na HPTEC que o trombo retirado por TEAP é composto por células endoteliais, musculares e miofibroblastos (2) , e acredita-se que essas células teriam características diferentes de células de artérias pulmonares sem doença. Seriam mais resistentes à apoptose por perda da sinalização de sua sobrevivência (20) ; consequentemente, teriam um estímulo à proliferação desordenada (21) , semelhante ao que ocorre em pacientes com HAP idiopática (22) .…”

Section: Mecanismos Fisiopatológicos Da Hptecunclassified

“…Quando se analisa a circulação sistêmica, o fluxo elevado (³ 15 dynes/cm 2 ), chamado de cisalhamento laminar, confere proteção, e o oscilatório, que é o baixo (< 5 dynes/cm 2 ), pode promover disfunção endotelial, contribuindo para a doença cardiovascular(17,18) . Esta tensão de cisalhamento também é identificada na artéria pulmonar, como demonstrado na Figura 1(19) ; entretanto, o alto fluxo acarreta um efeito oposto ao sistêmico, induzindo agravamento da doença, remodelamento vascular com disfunção endotelial(9) .1 Introdução…”

unclassified

Alterações na proteostase de células endoteliais pulmonares em pacientes com hipertensão pulmonar tromboembólica crônica

Filho¹

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Reconciling paradigms of abnormal pulmonary blood flow and quasi-malignant cellular alterations in pulmonary arterial hypertension

Cited by 9 publications

References 150 publications

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

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

Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice

Alterações na proteostase de células endoteliais pulmonares em pacientes com hipertensão pulmonar tromboembólica crônica

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