Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension

Bonnet, Sébastien; Provencher, Steeve; Guignabert, Christophe; Perros, Frédèric; Boucherat, Olivier; Schermuly, Ralph Theo; Hassoun, Paul M.; Rabinovitch, Marlene; Nicolls, Mark R.; Humbert, Marc

doi:10.1164/rccm.201607-1515pp

Cited by 120 publications

(98 citation statements)

References 129 publications

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“…Alternatively, when studying molecular mechanisms behind the progression from compensated RVH to RVF, PAB with various degrees and/or durations of banding is preferable. Corroboration of results in more than one model strengthens experimental findings (70). The RV Langendorff model is a useful ex vivo model to assess RV inotropy and lusitropy (71-73) and a useful adjunct to in vivo assessments of the RV, which are largely load dependent.…”

Section: Optimization Of Animal Models Of Rvfmentioning

confidence: 57%

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement

Lahm

Douglas²,

Archer³

et al. 2018

Am J Respir Crit Care Med

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Section: Optimization Of Animal Models Of Rvfmentioning

confidence: 57%

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement

Lahm

Douglas²,

Archer³

et al. 2018

Am J Respir Crit Care Med

Self Cite

260

247

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“…42 Studying the coronary vasculature should be included in new preclinical research to better predict patients' outcome, which is already challenging. 43 Needless to say that aside from the pathogenic SMCs, endothelial cell dysfunction also contributes to vascular remodeling processes. 44 Indeed, the endothelium is important for cardiovascular health, as it provides a protective layer, regulates vascular tone, and blood vessel growth.…”

Section: Discussionmentioning

confidence: 99%

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

Meloche

Lampron

Nadeau

et al. 2017

ATVB

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P ulmonary arterial hypertension (PAH) is a vascularremodeling disease (VRD) first described as an obstructive pathology affecting the distal pulmonary arteries. It is characterized by enhanced inflammation, vasoconstriction, and proliferation/apoptosis imbalance within the arterial wall, leading to increased pulmonary vascular resistance and right ventricular (RV) failure and death. 1 The smooth muscle cells (SMCs) within the pulmonary arterial wall exhibit exaggerated proliferation and resistance to apoptosis. Many groups have studied the underlying mechanisms of this "cancer-like" phenotype to find better ways to treat this deadly disease. The similarities in histological features between PAH and other VRDs suggest common pathogenic mechanisms. We and others have described the implication of the receptor of advanced glycation endproducts, 2-4 the oncoprotein kinase Pim-1 3, 5 and the transcription factor nuclear factor of activated T cells 6,7 in promoting proliferation in remodeling processes occurring in both VRD and PAH. In PAH patients' lung vasculature, these molecular actors are, at least in part, regulated by proinflammatory cytokines, alterations in the miR-223/DNA damage/ Poly[ADP-ribose] polymerase 1/miR-204 axis 8-11 and subsequent overexpression of the epigenetic reader bromodomain protein 4 (BRD4). 12 BRD4 functions as a scaffold for transcription factors at promoters and superenhancers, modulating the chromatin landscape and facilitating transcriptional activation of target genes. 13 Interestingly, BRD4 is also implicated in systemic VRD by triggering proinflammatory endothelial © 2017 American Heart Association, Inc. Objective-Pulmonary arterial hypertension (PAH) is a vascular disease not restricted to the lungs. Many signaling pathways described in PAH are also of importance in other vascular remodeling diseases, such as coronary artery disease (CAD). Intriguingly, CAD is 4× more prevalent in PAH compared with the global population, suggesting a link between these 2 diseases. Both PAH and CAD are associated with sustained inflammation and smooth muscle cell proliferation/ apoptosis imbalance and we demonstrated in PAH that this phenotype is, in part, because of the miR-223/DNA damage/ Poly[ADP-ribose] polymerase 1/miR-204 axis activation and subsequent bromodomain protein 4 (BRD4) overexpression. Interestingly, BRD4 is also a trigger for calcification and remodeling processes, both of which are important in CAD. Thus, we hypothesize that BRD4 activation in PAH influences the development of CAD. Approach and Results-PAH was associated with significant remodeling of the coronary arteries in both human and experimental models of the disease. As observed in PAH distal pulmonary arteries, coronary arteries of patients with PAH also exhibited increased DNA damage, inflammation, and BRD4 overexpression. In vitro, using human coronary artery smooth muscle cells from PAH, CAD and non-PAH-non-CAD patients, we showed that both PAH and CAD smooth muscle cells exhibited increased proliferation and suppres...

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“…). These results indicated that miR-140-5p played a negative regulation role in the TNF-α expression and they could regulate TNF signaling pathway-related protein activation, such as the phosphorylation of IkBα and p38 and inhibit PAH pathogenesis.3.7 | miR-140-5p and TNF-α modulated PASMCs proliferation, migration, and phenotype in PASMCs in hypoxia conditionSince PASMCs are a vital cell type contributing to pulmonary vascular remodeling, and in a hypoxia condition, they will perform uncontrolled proliferation and migration(Bonnet et al, 2017;Pietra et al, 2004), we confirmed if miR-140-5p inhibits PASMCs proliferation, migration phenotypic variation by targeting TNF-α in hypoxiamediated PASMCs. To analyze the proliferation of PASMCs, the expression of PCNA, which is a cell proliferative marker(de Paula Nascimento-Castro et al, 2018), was measured by western blot and EdU assay was performed under hypoxic environment.…”

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confidence: 99%

MicroRNA‐140‐5p targeting tumor necrosis factor‐α prevents pulmonary arterial hypertension

Zhu

Zhang

Yin

et al. 2018

Journal Cellular Physiology

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Background Pulmonary arterial hypertension (PAH) is characterized by the apoptosis resistance and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Its pathogenesis has not been revealed. Here, we carried out experiments to investigate the functions of miR‐140‐5p and tumor necrosis factor‐α (TNF‐α). Methods We selected GSE703 from Gene Expression Omnibus (GEO) Database to conduct microarray analysis using R software and Gene Set Enrichment Analysis (GSEA). Combing bioinformatics results, the upregulation of miR‐140‐5p inhibited PAH progression through targeting TNF‐α. RNA expression was measured by quantitative real‐time polymerase chain reaction (RT‐qPCR) and protein level was measured by western blot analysis and enzyme‐linked immunosorbent assays (ELISA). We conducted monocrotaline (MCT) injection to rats to form PAH animal models. The lung tissues were observed by hematoxylin–eosin (HE) staining and Sirius red‐picric acid staining. Right ventricular systolic pressure (RVSP) and the ratio of right ventricle (RV)‐to‐left ventricle (LV) plus septum (S) weight (RV/[LV + S]) were measured in MCT‐induced animal models. Overexpression of miR‐140‐5p and TNF‐α were utilized to research the proliferation, migration, and phenotypic variation of hypoxia‐mediated PASMCs. The binding between miR‐140‐5p and TNF‐α 3′‐untranslated region (3′‐UTR) was confirmed via luciferase reporter assay. Results Downregulation of miR‐140‐5p and upregulation of TNF‐α were observed in PAH rat model and hypoxia‐mediated PASMCs. And we proved that overexpression of miR‐140‐5p could suppress the proliferation, migration, and phenotypic variation of PASMCs, therefore inhibiting PAH pathogenesis. Luciferase assay verified that miR‐140‐5p targeted TNF‐α directly. A converse correlation was also shown between miR‐140‐5p and TNF‐α in PASMCs. Conclusions miR‐140‐5p and TNF‐α are important regulators in PAH pathology and may serve as a therapeutic target for PAH.

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Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension

Cited by 120 publications

References 129 publications

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

MicroRNA‐140‐5p targeting tumor necrosis factor‐α prevents pulmonary arterial hypertension

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