Critical effects of epigenetic regulation in pulmonary arterial hypertension

Hereditary hemorrhagic telangiectasia (HTT) is an autosomal dominant disease, most frequently caused by a mutation in either ENG or ACVRL1, which can be associated with pulmonary arterial hypertension (PAH). In this report, we describe a new unpublished ACVRL1 mutation segregating in three members of the same family, showing three different types of pulmonary hypertension (PH) in the absence of BMPR2 mutations. The first patient has a form of heritable PAH (HPAH) in the absence of hepatic arteriovenous malformations (AVMs); the second one has a severe form of portopulmonary hypertension (PoPAH) associated with multiple hepatic AVMs; the third one has hepatopulmonary syndrome (HPS) with numerous hepatic arteriovenous fistulas and a form of post-capillary PH due to high cardiac output. In summary, a single mutation in the ACVRL1 gene can be associated, in the same family, with an extreme phenotypic variability regarding not only the clinical presentation of HHT but also the type of PH in the absence of BMPR2 mutations. More studies are needed to evaluate if this variability can be explained by the presence of additional variants in other genes relevant for the pathogenesis of HHT.

show abstract

“…Thus, it will be possible to explain, at least in part, the inter- and intra-familial phenotypic heterogeneity. 15 …”

Section: Discussionmentioning

confidence: 99%

Different forms of pulmonary hypertension in a family with clinical and genetic evidence for hereditary hemorrhagic teleangectasia type 2

Greco

Plumitallo²,

Maggi

et al. 2018

Pulm. circ.

View full text Add to dashboard Cite

show abstract

“…e Migration ability of hypoxia-induced PASMCs was analyzed using wound healing assay, and results were presented as the average of three independent replicates. *P < 0.05, **P < 0.01, ***P < 0.001 various pathogenic pathways, such as those underlying cardiovascular diseases and PAH [25]. For instance, LncRNA Hoxaas3 contributed to the proliferation of hypoxiainduced PASMCs and modulated cell cycle distribution in PH [26].…”

Section: Serum Casc2 May Be a Potential Circulating Biomarker For Pahmentioning

confidence: 98%

LncRNA CASC2 inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation and migration by regulating the miR-222/ING5 axis

et al. 2020

View full text Add to dashboard Cite

Background: Pulmonary arterial hypertension (PAH) is often characterized by cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). LncRNA cancer susceptibility candidate 2 (CASC2) has been revealed to be involved in PASMC injury in hypoxia-induced pulmonary hypertension. However, the exact molecular mechanisms whereby CASC2 regulates PASMC proliferation and migration are still incompletely understood. Methods: The expression levels of CASC2, miR-222 and inhibitor of growth 5 (ING5) were measured using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot, respectively. Cell proliferation was analyzed by Cell Counting Kit-8 (CCK-8) assay. Wound healing assay was used to analyze cell migration ability. The relationship between miR-222 and CASC2 or ING5 was confirmed using bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation assay. Results: CASC2 was down-regulated in hypoxia-induced PASMCs in a dose-and time-dependent manner. Functional experiments showed that CASC2 overexpression could reverse hypoxia-induced proliferation and migration of PASMCs. Bioinformatics analysis indicated that CASC2 acted as a competing endogenous RNA of miR-222, thereby regulating the expression of ING5, the downstream target of miR-222, in PASMCs. In addition, rescue assay suggested that the inhibition mediated by CASC2 of hypoxia-induced PASMC proliferation and migration could be attenuated by miR-222 inhibition or ING5 overexpression. Conclusion: CASC2 attenuated hypoxia-induced PASMC proliferation and migration by regulating the miR-222/ING5 axis to prevent vascular remodeling and the development of PAH, providing a novel insight and therapeutic strategy for hypoxiainduced PAH.

show abstract

“…In contrast to the systemic circulation, the pulmonary circuit is a high-flow, low-pressure system, and despite the lower pressure within the pulmonary circulation, small increases in pulmonary arterial pressure can result in severe cardiovascular dysfunction (2,22). While there are a variety of factors involved in the pathogenesis of pulmonary HT, the defining features include vasoconstriction and muscularization of distal pulmonary arteries that lead to increased pulmonary vascular resistance and ultimately right ventricular hypertrophy and failure (6,22,24). Cellularly, the remodeling of pulmonary vessels results from a shift toward a hyperproliferative, antiapoptotic, and proinflammatory state in cells of the pulmonary vascular wall (24).…”

Section: Chromatin-remodeling Complexes and The Postnatal Vasculaturementioning

confidence: 99%

ATP-dependent chromatin remodeling complexes in embryonic vascular development and hypertension

Crosswhite

2019

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Hypertension, a chronic elevation in blood pressure, is the largest single contributing factor to mortality worldwide and the most common preventable risk factor for cardiovascular disease. High blood pressure increases the risk for someone to experience a number of adverse cardiovascular events including heart failure, stroke, or aneurysm. Despite advancements in understanding factors that contribute to hypertension, the etiology remains elusive and there remains a critical need to develop innovative study approaches to develop more effective therapeutics. ATP-dependent chromatin remodelers are dynamic regulators of DNA-histone bonds and thus gene expression. The goal of this review is to highlight and summarize reports of ATP-dependent chromatin remodelers contribution to the development or maintenance of hypertension. Emerging evidence from hypertensive animal models suggests that induction of chromatin remodeler activity increases proinflammatory genes and increases blood pressure, whereas human studies demonstrate how chromatin remodelers may act as stress-response sensors to harmful physiological stimuli. Importantly, genomic studies have linked patients with hypertension to mutations in chromatin remodeler genes. Collectively, evidence linking chromatin remodelers and hypertension warrants additional research and ultimately could reveal novel therapeutic approaches for treating this complex and devastating disease.

show abstract

Critical effects of epigenetic regulation in pulmonary arterial hypertension

Cited by 13 publications

References 157 publications

Different forms of pulmonary hypertension in a family with clinical and genetic evidence for hereditary hemorrhagic teleangectasia type 2

Different forms of pulmonary hypertension in a family with clinical and genetic evidence for hereditary hemorrhagic teleangectasia type 2

LncRNA CASC2 inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation and migration by regulating the miR-222/ING5 axis

ATP-dependent chromatin remodeling complexes in embryonic vascular development and hypertension

Contact Info

Product

Resources

About