TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

Rol, Nina; Kurakula, Kondababu; Happé, Chris; Bogaard, Harm Jan; Goumans, Marie–José

doi:10.3390/ijms19092585

Cited by 93 publications

(72 citation statements)

References 134 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Upon binding to bone morphogenetic proteins (BMPs), BMPR2 initiates intracellular signaling that ultimately leads to the inhibition of proliferation of vascular smooth muscle tissue. In smooth muscle cells, BMP signaling can be directly inhibited by TGF-β signaling and involved ligands are able to function as antagonists in competition for type II receptor binding [123]. BMPR2 loss-of-function mutations are a known cause for PAH development in patients and lead to more severe disease and increased risk of death when compared to PAH patients without a BMPR2 mutation [124].…”

Section: Immunomodulatory Therapy In Pah and Ctephmentioning

confidence: 99%

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Koudstaal

Boomars

Kool

2020

JCM

View full text Add to dashboard Cite

Pulmonary hypertension (PH) is a debilitating progressive disease characterized by increased pulmonary arterial pressures, leading to right ventricular (RV) failure, heart failure and, eventually, death. Based on the underlying conditions, PH patients can be subdivided into the following five groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) PH due to lung disease, (4) chronic thromboembolic PH (CTEPH), and (5) PH with unclear and/or multifactorial mechanisms. Currently, even with PAH-specific drug treatment, prognosis for PAH and CTEPH patients remains poor, with mean five-year survival rates of 57%–59% and 53%–69% for PAH and inoperable CTEPH, respectively. Therefore, more insight into the pathogenesis of PAH and CTEPH is highly needed, so that new therapeutic strategies can be developed. Recent studies have shown increased presence and activation of innate and adaptive immune cells in both PAH and CTEPH patients. Moreover, extensive biomarker research revealed that many inflammatory and immune markers correlate with the hemodynamics and/or prognosis of PAH and CTEPH patients. Increased evidence of the pathological role of immune cells in innate and adaptive immunity has led to many promising pre-clinical interventional studies which, in turn, are leading to innovative clinical trials which are currently being performed. A combination of immunomodulatory therapies might be required besides current treatment based on vasodilatation alone, to establish an effective treatment and prevention of progression for this disease. In this review, we describe the recent progress on our understanding of the involvement of the individual cell types of the immune system in PH. We summarize the accumulating body of evidence for inflammation and immunity in the pathogenesis of PH, as well as the use of inflammatory biomarkers and immunomodulatory therapy in PAH and CTEPH.

show abstract

Section: Immunomodulatory Therapy In Pah and Ctephmentioning

confidence: 99%

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Koudstaal

Boomars

Kool

2020

JCM

View full text Add to dashboard Cite

show abstract

“…Although the pathogenesis of PAH is not completely understood, it has been reported that the genetic change resulting in endothelial dysfunction is an important contributing factor (2,3). Previous studies have revealed that bone morphogenetic protein type II receptor (BMPR2) mutations serve an important role in PAH pathogenesis via the Smad and transforming growth factor-β signaling pathways (4)(5)(6). However, as PAH is not penetrant, BMPR2 mutations alone may not be sufficient to cause disease, therefore, other genetic and/or non-genetic factors may serve as a 'second hit' to trigger PAH pathology (7), including inflammation and chronic hypoxia.…”

Section: Introductionmentioning

confidence: 99%

SIRT1 promotes pulmonary artery endothelial cell proliferation by targeting the Akt signaling pathway

Ruan

Yao

et al. 2020

Exp Ther Med

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a disease characterized by a progressive increase in pulmonary vascular resistance and obliterative pulmonary vascular remodeling; however, the pathogenesis of the disease is not completely understood. Sirtuin 1 (SIRT1) is a histone deacetylase involved in cell survival and metabolism. The present study explored the potential role of SIRT1 in human pulmonary arterial endothelial cells (HPAECs) under hypoxic conditions. In vitro HPAECs were cultured and exposed to hypoxic conditions. Subsequently, SIRT1 expression levels were measured via western blotting, the generation of reactive oxygen species (ROS) was evaluated, and the interaction between SIRT1 and Akt was assessed via reverse transcription-quantitative PCR and western blotting. In addition, the effects of SIRT1 on cell proliferation and apoptosis were also investigated. The results indicated that hypoxia induced SIRT1 expression in pulmonary arterial endothelial cells, which may be associated with ROS generation. SIRT1 expression activated the Akt signaling pathway, which increased the expression levels of Bcl-2 and hypoxia-inducible factor-1 in HPAECs. Moreover, SIRT1 promoted HPAEC proliferation and inhibited HPAEC apoptosis. ROS generation enhanced the SIRT1/Akt axis, which was essential for epithelial cell injury under hypoxic conditions. Therefore, blocking SIRT1 may reduce hypoxia-induced pathological damage in HPAECs.

show abstract

“…increased glucose uptake and utilization by glycolysis and the pentose shunt in diseased pASMcs. We began by assessing the uptake and utilization of [1,2,[3][4][5][6][7][8][9][10][11][12][13] C 3 ]glucose in diseased versus control PASMCs. Glucose labeled at carbons 1-3 allows the comparative assessment of glucose metabolism through glycolysis versus the pentose shunt.…”

Section: Resultsmentioning

confidence: 99%

“…www.nature.com/scientificreports www.nature.com/scientificreports/ disease and schistosomiasis [11][12][13] . TGF-β induces cellular phenotypes which require energy and metabolic substrates, including proliferation, migration, contraction, and synthesis of cytokines and the extracellular matrix.…”

mentioning

confidence: 99%

Stable isotope metabolomics of pulmonary artery smooth muscle and endothelial cells in pulmonary hypertension and with TGF-beta treatment

Hernández-Saavedra

Sanders

Freeman

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Altered metabolism in pulmonary artery smooth muscle cells (pASMcs) and endothelial cells (pAecs) contributes to the pathology of pulmonary hypertension (pH), but changes in substrate uptake and how substrates are utilized have not been fully characterized. We hypothesized stable isotope metabolomics would identify increased glucose, glutamine and fatty acid uptake and utilization in human pASMcs and pAecs from pH versus control specimens, and that tGf-β treatment would phenocopy these metabolic changes. We used 13 c-labeled glucose, glutamine or a long-chain fatty acid mixture added to cell culture media, and mass spectrometry-based metabolomics to detect and quantify 13 c-labeled metabolites. We found pH pASMcs had increased glucose uptake and utilization by glycolysis and the pentose shunt, but no changes in glutamine or fatty acid uptake or utilization. Diseased pAecs had increased proximate glycolysis pathway intermediates, less pentose shunt flux, increased anaplerosis from glutamine, and decreased fatty acid β-oxidation. tGf-β treatment increased glycolysis in pASMcs, but did not recapitulate the pAec disease phenotype. in tGf-β-treated pASMcs, glucose, glutamine and fatty acids all contributed carbons to the tcA cycle. in conclusion, pASMcs and pAecs collected from pH subjects have significant changes in metabolite uptake and utilization, partially recapitulated by TGF-β treatment. Changes in cellular metabolism are increasingly recognized as a hallmark of pulmonary hypertension (PH) pathobiology 1-4. Shifts in the uptake of metabolic substrates and how they are utilized downstream enables the disease phenotype of vascular cells in PH, including increased proliferation, apoptosis resistance, hypertrophy and vasoconstriction 3. One critical metabolic shift observed in PH is an increase in glycolysis, which is thought to occur in resident vascular wall cells including pulmonary artery smooth muscle cells (PASMCs), endothelial cells (PAECs) and fibroblasts 5-7. Increased glucose uptake can be demonstrated in vivo by increased uptake of the glucose analog 18 F-fluorodeoxyglucose in the lung parenchyma of PH subjects 6,8. The concept that glycolysis in PH is detrimental has led to investigation of the potential utility of dichloroacetate (DCA), which by blocking pyruvate dehydrogenase kinase causes increased glucose flux into the TCA cycle, and less glycolysis 9. Glutamine uptake and metabolism by PAECs has also been shown to contribute to their disease phenotype 10. However, comprehensive assessment of substrate uptake and how the substrates are utilized by pulmonary vascular cells in PH is lacking. A potential driver of altered cellular metabolism is transforming growth factor β (TGF-β) signaling, which underlies many forms of heritable (through mutations in BMPR2 and other members of the TGF-β signaling superfamily) and idiopathic PAH, and PAH etiologies associated with other conditions such as autoimmune

show abstract

TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

Cited by 93 publications

References 134 publications

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

SIRT1 promotes pulmonary artery endothelial cell proliferation by targeting the Akt signaling pathway

Stable isotope metabolomics of pulmonary artery smooth muscle and endothelial cells in pulmonary hypertension and with TGF-beta treatment

Contact Info

Product

Resources

About