Epigenetic regulation of pulmonary arterial hypertension

Xu, Xuefeng; Cheng, Fen; Du, Lizhong

doi:10.1038/hr.2011.79

Cited by 21 publications

(12 citation statements)

References 87 publications

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“…It is characterized by elevated pulmonary arterial pressures (PAP), and increased pulmonary vascular resistance leading to right-sided heart failure and death [1], [7]. Evidence reveals that epigenetic alterations may be involved in PAH such as changes in the phenotype or in gene expression states, including chromatin remodeling, DNA methylation and histone modifications [28]. The importance of EZH2 in the proliferation of HPASMCs and its implications in the development of PAH is demonstrated for the first time.…”

Section: Discussionmentioning

confidence: 99%

Enhancer of Zeste Homolog 2 Induces Pulmonary Artery Smooth Muscle Cell Proliferation

et al. 2012

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IntroductionPulmonary Arterial Hypertension (PAH) is a progressively devastating disease characterized by excessive proliferation of the Pulmonary Arterial Smooth Muscle Cells (PASMCs). Studies suggest that PAH and cancers share an apoptosis-resistant state featuring excessive cell proliferation. The proliferation of cancer cells is mediated by increased expression of Enhancer of Zeste Homolog 2 (EZH2), a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes. However, the role of EZH2 in PAH has not been studied. In this study, it is hypothesized that EZH2 could play a role in the proliferation of PASMCs.MethodsIn the present study, the expression patterns of EZH2 were investigated in normal and hypertensive mouse PASMCs. The effects of EZH2 overexpression on the proliferation of human PASMCs were tested. PASMCs were transfected with EZH2 or GFP using nucleofector system. After transfection, the cells were incubated for 48 hours at 37°C. Proliferation and cell cycle analysis were performed using flow cytometry. Apoptosis of PASMCs was determined using annexin V staining and cell migration was tested by wound healing assay.ResultsEZH2 protein expression in mouse PASMCs were correlated with an increase in right ventricular systolic pressure and Right Ventricular Hypertrophy (RVH). The overexpression of EZH2 in human PASMCs enhances proliferation, migration, and decrease in the rate of apoptosis when compared to GFP-transfected cells. In the G2/M phase of the EZH2 transfected cells, there was a 3.5 fold increase in proliferation, while there was a significant decrease in the rate of apoptosis of PASMCs, when compared to control.ConclusionThese findings suggest that EZH2 plays a role in the migration and proliferation of PASMCs, which is a major hallmark in PAH. It also suggests that EZH2 could play a role in the development of PAH and can serve as a potential target for new therapies for PAH.

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Section: Discussionmentioning

confidence: 99%

Enhancer of Zeste Homolog 2 Induces Pulmonary Artery Smooth Muscle Cell Proliferation

et al. 2012

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“…Recently identified race-and sex differences in the effects of ERA therapy in PAH patients (Gabler et al, 2012), ERA-drug interactions (Venitz et al, 2012) (Pulido et al, 2009;Srinivas, 2009;Walker et al, 2009;Harrison et al, 2010;Spangler and Saxena, 2010), and epigenetic regulation in PAH (Xu et al, 2011) require further clinical research.…”

Section: Current Perspectives For Era Therapy In Clinical Medicinementioning

confidence: 98%

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

et al. 2012

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In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials - except those for pulmonary arterial hypertension and scleroderma-related digital ulcers - were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused.

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“…However, the increased eNOS expression did not completely offset the effect of vasoconstrictors, such as endothelin-1 (ET-1), and subsequent development of PPHN [19,20]. A number of clinical studies demonstrated that increased ET-1 was strongly associated with PAH [21-23].…”

Section: Introductionmentioning

confidence: 99%

Epigenetics of hypoxic pulmonary arterial hypertension following intrauterine growth retardation rat: epigenetics in PAH following IUGR

et al. 2013

Respir Res

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BackgroundAccumulating evidence reveals that intrauterine growth retardation (IUGR) can cause varying degrees of pulmonary arterial hypertension (PAH) later in life. Moreover, epigenetics plays an important role in the fetal origin of adult disease. The goal of this study was to investigate the role of epigenetics in the development of PAH following IUGR.MethodsThe IUGR rats were established by maternal undernutrition during pregnancy. Pulmonary vascular endothelial cells (PVEC) were isolated from the rat lungs by magnetic-activated cell sorting (MACS). We investigated epigenetic regulation of the endothelin-1 (ET-1) gene in PVEC of 1-day and 6-week IUGR rats, and response of IUGR rats to hypoxia.ResultsThe maternal nutrient restriction increased the histone acetylation and hypoxia inducible factor-1α (HIF-1α) binding levels in the ET-1 gene promoter of PVEC in IUGR newborn rats, and continued up to 6 weeks after birth. These epigenetic changes could result in an IUGR rat being highly sensitive to hypoxia later in life, causing more significant PAH or pulmonary vascular remodeling.ConclusionsThese findings suggest that epigenetics is closely associated with the development of hypoxic PAH following IUGR, further providing a new insight for improved prevention and treatment of IUGR-related PAH.

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Epigenetic regulation of pulmonary arterial hypertension

Cited by 21 publications

References 87 publications

Enhancer of Zeste Homolog 2 Induces Pulmonary Artery Smooth Muscle Cell Proliferation

Enhancer of Zeste Homolog 2 Induces Pulmonary Artery Smooth Muscle Cell Proliferation

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

Epigenetics of hypoxic pulmonary arterial hypertension following intrauterine growth retardation rat: epigenetics in PAH following IUGR

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