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Role of RASEF hypermethylation in cigarette smoke-induced pulmonary arterial smooth muscle remodeling.

ABSTRACT: BACKGROUND:Pulmonary hypertension (PH) is a progressive and fatal disease. While cigarette smoke can change DNA methylation status, the role of such molecular alterations in smoke-associated PH is unclear. METHODS:A PH rat model was developed by exposing animals to cigarette smoke for 3?months. Right ventricular systolic pressure was measured with a right heart catheter. Histological changes (right ventricular hypertrophy index, medial wall thickness in pulmonary arteries (PAs)) and DNMT1 protein levels in rat PAs or primary human PA smooth muscle cells (HPASMCs) exposed to cigarette smoke extract were assessed. Methylation sequencing and MassArray® were used to detect genomic and RASEF promoter methylation status, respectively. After DNMT1 knockdown and cigarette smoke extract exposure, HPASMCs behavior (proliferation, migration) and RASEF methylation status were examined; RASEF mRNA expression was evaluated by real-time-polymerase chain reaction. RASEF overexpression viral vectors were used to assess the impact of RASEF on rat PH and HPASMCs remodeling. RESULTS:Higher right ventricular systolic pressure, medial wall thickness, and right ventricular hypertrophy index values were observed in the smoking group rats. Smoke exposure increased DNMT1 expression and RASEF methylation levels in rat PAs and HPASMCs. Cigarette smoke extract induced HPASMCs behavioral changes and RASEF hypermethylation followed by silencing, while DNMT1 knockdown markedly inhibited these changes. RASEF overexpression distinctly inhibited PH and HPASMCs remodeling, possibly through phospho-AKT (Ser473), PCNA, and MMP9 downregulation. CONCLUSIONS:Cigarette smoke caused PA remodeling in PH rats related to RASEF hypermethylation. These results expand our understanding of key epigenetic mechanisms in cigarette smoke-associated PH and potentially provide a novel therapeutic target for PH.

SUBMITTER: Li Q

PROVIDER: S-EPMC6407244 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Role of RASEF hypermethylation in cigarette smoke-induced pulmonary arterial smooth muscle remodeling.

Li Qinghai Q Wu Jixing J Xu Yongjian Y Liu Lu L Xie Jungang J

Respiratory research 20190307 1

<h4>Background</h4>Pulmonary hypertension (PH) is a progressive and fatal disease. While cigarette smoke can change DNA methylation status, the role of such molecular alterations in smoke-associated PH is unclear.<h4>Methods</h4>A PH rat model was developed by exposing animals to cigarette smoke for 3 months. Right ventricular systolic pressure was measured with a right heart catheter. Histological changes (right ventricular hypertrophy index, medial wall thickness in pulmonary arteries (PAs)) a ...[more]

PMID: 30845941

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Project description:Rationale: Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). It remains unknown how glycolysis is increased and how increased glycolysis contributes to pulmonary vascular remodeling in PAH.Objectives: To determine whether increased glycolysis is caused by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and how PFKFB3-driven glycolysis induces vascular remodeling in PAH.Methods: PFKFB3 levels were measured in pulmonary arteries of patients and animals with PAH. Lactate levels were assessed in lungs of animals with PAH and in pulmonary artery smooth muscle cells (PASMCs). Genetic and pharmacologic approaches were used to investigate the role of PFKFB3 in PAH.Measurements and Main Results: Lactate production was elevated in lungs of PAH rodents and in platelet-derived growth factor-treated PASMCs. PFKFB3 protein was higher in pulmonary arteries of patients and rodents with PAH, in PASMCs of patients with PAH, and in platelet-derived growth factor-treated PASMCs. PFKFB3 inhibition by genetic disruption and chemical inhibitor attenuated phosphorylation/activation of extracellular signal-regulated kinase (ERK1/2) and calpain-2, and vascular remodeling in PAH rodent models, and reduced platelet-derived growth factor-induced phosphorylation/activation of ERK1/2 and calpain-2, collagen synthesis and proliferation of PASMCs. ERK1/2 inhibition attenuated phosphorylation/activation of calpain-2, and vascular remodeling in Sugen/hypoxia PAH rats, and reduced lactate-induced phosphorylation/activation of calpain-2, collagen synthesis, and proliferation of PASMCs. Calpain-2 inhibition reduced lactate-induced collagen synthesis and proliferation of PASMCs.Conclusions: Upregulated PFKFB3 mediates collagen synthesis and proliferation of PASMCs, contributing to vascular remodeling in PAH. The mechanism is through the elevation of glycolysis and lactate that results in the activation of calpain by ERK1/2-dependent phosphorylation of calpain-2.

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Role of RASEF hypermethylation in cigarette smoke-induced pulmonary arterial smooth muscle remodeling.

Publications

Role of RASEF hypermethylation in cigarette smoke-induced pulmonary arterial smooth muscle remodeling.

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