Effects of an endothelin receptor antagonist, Macitentan, on right ventricular substrate utilization and function in a Sugen 5416/hypoxia rat model of severe pulmonary arterial hypertension

Drozd, Katarzyna; Ahmadi, Ali; Deng, Yupu; Jiang, Baohua; Petryk, Julia; Thorn, Stephanie; Stewart, Duncan J.; Beanlands, Rob; deKemp, Robert A.; DaSilva, Jean N.; Mielniczuk, Lisa

doi:10.1007/s12350-016-0663-4

Cited by 21 publications

(16 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 9 Interestingly, macitentan was recently associated with metabolic changes in the RV of Sugen-induced PAH. 57 Consistent with this hypothesis, dual ET A /ET B receptor blockade also impacted on capillary density and perfusion within the RV and skeletal muscles in our PH model. However, part of the increases in perfusion (i.e.…”

Section: Discussionsupporting

confidence: 86%

“…Given the tight coupling between angiogenesis and metabolism, 13 the metabolic dysregulation observed within the distal PA, RV, 9 and skeletal muscles 10 in PAH has been hypothesized to contribute to this capillary rarefaction in PAH 9 . Interestingly, macitentan was recently associated with metabolic changes in the RV of Sugen‐induced PAH 57 . Consistent with this hypothesis, dual ET A /ET B receptor blockade also impacted on capillary density and perfusion within the RV and skeletal muscles in our PH model.…”

Section: Discussionsupporting

confidence: 84%

See 1 more Smart Citation

Dual ET_A/ET_B blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

et al. 2017

View full text Add to dashboard Cite

Dysregulated metabolism and rarefaction of the capillary network play a critical role in pulmonary arterial hypertension (PAH) etiology. They are associated with a decrease in perfusion of the lungs, skeletal muscles, and right ventricle (RV). Previous studies suggested that endothelin-1 (ET-1) modulates both metabolism and angiogenesis. We hypothesized that dual ETA/ETB receptors blockade improves PAH by improving cell metabolism and promoting angiogenesis. Five weeks after disease induction, Sugen/hypoxic rats presented severe PAH with pulmonary artery (PA) remodeling, RV hypertrophy and capillary rarefaction in the lungs, RV, and skeletal muscles (microCT angiogram, lectin perfusion, CD31 staining). Two-week treatment with dual ETA/ETB receptors antagonist macitentan (30 mg/kg/d) significantly improved pulmonary hemodynamics, PA vascular remodeling, and RV function and hypertrophy compared to vehicle-treated animals (all P = 0.05). Moreover, macitentan markedly increased lung, RV and quadriceps perfusion, and microvascular density (all P = 0.05). In vitro, these effects were associated with increases in oxidative phosphorylation (oxPhox) and markedly reduced cell proliferation of PAH-PA smooth muscle cells (PASMCs) treated with macitentan without affecting apoptosis. While macitentan did not affect oxPhox, proliferation, and apoptosis of PAH–PA endothelial cells (PAECs), it significantly improved their angiogenic capacity (tube formation assay). Exposure of control PASMC and PAEC to ET-1 fully mimicked the PAH cells phenotype, thus confirming that ET-1 is implicated in both metabolism and angiogenesis abnormalities in PAH. Dual ETA/ETB receptor blockade improved the metabolic changes involved in PAH-PASMCs’ proliferation and the angiogenic capacity of PAH-PAEC leading to an increased capillary density in lungs, RV, and skeletal muscles.

show abstract

Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 84%

Dual ET_A/ET_B blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

et al. 2017

View full text Add to dashboard Cite

show abstract

“…PET studies have shown substantial increases in 18 FDG uptake in the RV of both animals and humans with RV hypertrophy [ 90 ] and PAH [ 79 , 90 – 92 ] ( figure 3a ). More recent studies have determined that such increased RV 18 FDG accumulation portends a poorer prognosis [ 97 ], while treatment with agents such as macitentan can attenuate such uptake concomitant with an improvement in RV function and haemodynamics [ 98 ]. PET is useful for investigations into drug distribution, target binding and drug-induced biochemical responses; however, its cost and limited availability currently restricts its use.…”

Section: Diagnostic Application Of Metabolic Dysregulation In Phmentioning

confidence: 99%

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

Chan

Rubin

2017

Eur Respir Rev

View full text Add to dashboard Cite

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.

show abstract

“…Future perspectives beyond simple improvement in hemodynamics will focus on utilization of right-ventricle substrates and the effects of ERAs on right-ventricle remodeling and biventricular fibrosis. 76 , 77 In the near future, assessment of ERA efficacy on right-ventricle remodeling will rely increasingly on cardiac magnetic resonance imaging. Moreover, new ERAs will be tested (eg, HJP272), and other ERAs will be tested in diseases other than PAH (eg, chronic kidney disease, mainly for diabetic nephropathy).…”

Section: Future Developmentsmentioning

confidence: 99%

Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: where do we stand?

Correale

Ferraretti

Monaco

et al. 2018

VHRM

View full text Add to dashboard Cite

Pulmonary arterial hypertension, a disease largely neglected until a few decades ago, is presently the object of intense studies by several research teams. Despite considerable progress, pulmonary arterial hypertension remains a major clinical problem, because it is not always easy to diagnose, treat, and prevent. The disease was considered incurable until the late 1990s, when Epoprostenol was introduced as the first tool against this illness. More recently, therapy for pulmonary arterial hypertension gained momentum after publication of the SERAPHIN and AMBITION trials, which also highlighted the importance of upfront therapy. This review also focuses on recent substudies from these trials and progress in drugs targeting the endothelin pathway. Future perspectives with regard to endothelin-receptor antagonists are also discussed.

show abstract

Effects of an endothelin receptor antagonist, Macitentan, on right ventricular substrate utilization and function in a Sugen 5416/hypoxia rat model of severe pulmonary arterial hypertension

Abstract: PAH is associated with metabolic changes in the RV, characterized by a marked increase in FDG and FTHA uptake. Macitentan treatment reduced PAH severity and was associated with a decrease in RV FDG uptake and improved RV function.

Cited by 21 publications

References 29 publications

Dual ET_A/ET_B blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

Dual ET_A/ET_B blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

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

Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: where do we stand?

Contact Info

Product

Resources

About

Effects of an endothelin receptor antagonist, Macitentan, on right ventricular substrate utilization and function in a Sugen 5416/hypoxia rat model of severe pulmonary arterial hypertension

Abstract: PAH is associated with metabolic changes in the RV, characterized by a marked increase in FDG and FTHA uptake. Macitentan treatment reduced PAH severity and was associated with a decrease in RV FDG uptake and improved RV function.

Cited by 21 publications

References 29 publications

Dual ETA/ETB blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

Dual ETA/ETB blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

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

Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: where do we stand?

Contact Info

Product

Resources

About

Dual ET_A/ET_B blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

Dual ET_A/ET_B blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension