Key inflammatory pathways underlying vascular remodeling in pulmonary hypertension

Berghausen, Eva; Feik, L; Zierden, Mario; Vantler, Marius; Rosenkranz, Stephan

doi:10.1007/s00059-019-4795-6

Cited by 16 publications

(7 citation statements)

References 107 publications

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“…In addition, nuclear factor kappa B (NF-κB), which regulates the transcription and expression of multiple cytokines related to immunity and inflammation, exhibited significantly increased methylation in the T cell receptor signaling pathway, B cell receptor signaling pathway, chemokine signaling pathway and HIF-1 signaling pathway. Recent studies have shown that inflammation is closely related to vascular remodeling in PAH [ 40 ], suggesting that NF-κB may be involved in PAH by regulating the methylation of inflammatory factors.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of m6A mRNA methylation in rats with monocrotaline-induced pulmonary arterial hypertension

Zeng

Huang

Zuo

et al. 2021

Aging

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Background: N6-methyladenosine (m 6 A) modification is one of the most common chemical modifications of eukaryotic mRNAs, which play an important role in tumors and cardiovascular disease through regulating mRNA stability, splicing and translation. However, the changes of m 6 A mRNA and m 6 A-related enzymes in pulmonary arterial hypertension (PAH) remain largely unexplored. Methods: MeRIP-seq was used to identify m 6 A methylation in lung tissues from control and MCT-PAH rats. Western blot and immunofluorescence were used to evaluate expression of m 6 A-related enzymes. Results: Compared with control group, m 6 A methylation was mainly increased in lung tissues from MCT-PAH rats. The up-methylated coding genes in MCT-PAH rats were primarily enriched in processes associated with inflammation, glycolysis, ECM-receptor interaction and PDGF signal pathway, while genes with down-methylation were enriched in processes associated with TGF-β family receptor members. The expression of FTO and ALKBH5 downregulated, METTL3 and YTHDF1 increased and other methylation modification-related proteins was not significantly changed in MCT-PAH rats lung tissues. Immunofluorescence indicated that expression of FTO decreased and YTHDF1 increased in small pulmonary arteries of MCT-PAH rats. Conclusion: m 6 A levels and the expression of methylation-related enzymes were altered in PAH rats, in which FTO and YTHDF1 may play a crucial role in m 6 A modification.

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Section: Discussionmentioning

confidence: 99%

Integrated analysis of m6A mRNA methylation in rats with monocrotaline-induced pulmonary arterial hypertension

Zeng

Huang

Zuo

et al. 2021

Aging

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“…The online version of this article (https ://doi.org/10.1007/s0039 5-020-00826 -8) contains supplementary material, which is available to authorized users. inflammatory processes are linked to disease progression [8,16,20], and plasma levels of cyto-and chemokines such as interleukin (IL)-1β, IL-6, monocyte chemotactic protein (MCP)-1 and tumor necrosis factor (TNF)-α have prognostic value [3,21,39,42]). A potential source of increased circulating mediators are perivascular infiltrates of mononuclear cells that were described in the lung of PAH patients [9,29].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice

Batool¹,

Berghausen²,

Zierden³

et al. 2020

Basic Res Cardiol

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Six-transmembrane protein of prostate (Stamp2) protects from diabetes and atherosclerosis in mice via anti-inflammatory mechanisms. As chronic inflammation is a hallmark of pulmonary arterial hypertension (PAH), we investigated the role of Stamp2. Stamp2 expression was substantially reduced in the lung of humans with idiopathic PAH, as well as in experimental PAH. In Stamp2-deficient mice, hypoxia modestly aggravated pulmonary vascular remodeling and right ventricular pressure compared to WT. As endothelial cell (EC) and pulmonary arterial smooth muscle cell (PASMC) phenotypes drive remodeling in PAH, we explored the role of Stamp2. Knock-down of Stamp2 in human EC neither affected apoptosis, viability, nor release of IL-6. Moreover, Stamp2 deficiency in primary PASMC did not alter mitogenic or migratory properties. As Stamp2 deficiency augmented expression of inflammatory cytokines and numbers of CD68-positive cells in the lung, actions of Stamp2 in macrophages may drive vascular remodeling. Thus, PASMC responses were assessed following treatment with conditioned media of primary Stamp2−/− or WT macrophages. Stamp2−/− supernatants induced PASMC proliferation and migration stronger compared to WT. A cytokine array revealed CXCL12, MCP-1 and IL-6 as most relevant candidates. Experiments with neutralizing antibodies confirmed the role of these cytokines in driving Stamp2’s responses. In conclusion, Stamp2 deficiency aggravates pulmonary vascular remodeling via cross-talk between macrophages and PASMC. Despite a substantial pro-inflammatory response, the hemodynamic effect of Stamp2 deficiency is modest suggesting that additional mechanisms apart from inflammation are necessary to induce severe PAH.

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“… 12) For example, by focusing on inflammatory reactions, which are the main mechanisms of pulmonary vascular remodeling, anti-inflammatory remedies have an anti-remodeling role and modulate vascular tone, preventing vascular fibrosis. 13) Macrophages are one of the main actors inducing inflammation-related mediator cascades, and a treatment targeting monocytes, the precursors of these macrophages, and monocyte progenitors might be able to control pulmonary vascular remodeling. 14) 15) In addition, in these situations, pulmonary ECs and pulmonary arterial SMCs communicate, leading to remodeling of pulmonary vascularature called “plexiform”.…”

Section: Introductionmentioning

confidence: 99%

Stem Cell and Exosome Therapy in Pulmonary Hypertension

Jung

Ahn

et al. 2022

Korean Circ J

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Author's summary Pulmonary hypertension (PH) is a disease that eventually causes right heart failure by remodeling pulmonary blood vessels. Based on the histopathological characteristics, PH is categorized into five subgroups. Rarely, a severe clinical entity is pulmonary arterial hypertension (PAH), subgroup 1. This disease process results in pulmonary vascular alterations through dysfunction of the pulmonary endothelium and disturbance of immune responses. Although medical treatments based on these pathophysiologic concepts have been applied for more than 30 years, PAH still cannot be cured. This review addresses the feasibility of and perspectives on stem cell therapy, including the role of exosomes in PAH.

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Key inflammatory pathways underlying vascular remodeling in pulmonary hypertension

Cited by 16 publications

References 107 publications

Integrated analysis of m6A mRNA methylation in rats with monocrotaline-induced pulmonary arterial hypertension

Integrated analysis of m6A mRNA methylation in rats with monocrotaline-induced pulmonary arterial hypertension

The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice

Stem Cell and Exosome Therapy in Pulmonary Hypertension

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