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Protective effect of hydrogen sulfide on monocrotaline?induced pulmonary arterial hypertension via inhibition of the endothelial mesenchymal transition.

ABSTRACT: Endothelial?to?mesenchymal transition (EndMT) serves an important role in the vascular remodeling of pulmonary arterial hypertension (PAH). However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in PAH and the process of EndMT. Male Sprague?Dawley rats (10 weeks old) received a single dose of monocrotaline (MCT; i.p., 60 mg/kg) and were randomly treated with NaHS [an H2S donor; intraperitoneal (i.p.) 1 mg/kg/day], DL?propagylglycine (an inhibitor of H2S synthesis; PAG; i.p., 10 mg/kg/day) or saline, 7 days after MCT injection. Rats were sacrificed 21 days after MCT injection. A selection of human pulmonary artery endothelial cells (HPAECs) were pretreated with NaHS or saline and stimulated with transforming growth factor (TGF)??1 (10 ng/ml), and the other HPAECs were transfected with a cystathionine ??lyase (CSE, an H2S synthesizing enzyme) plasmid and subsequently stimulated with TGF??1. NaHS was indicated to inhibit EndMT and PAH progression by inhibiting the induction of the nuclear factor (NF)??B?Snail pathway. In contrast, the depletion of H2S formation by PAG exacerbated EndMT and PAH by activating NF??B?Snail molecules. In HPAECs, NaHS dose?dependently inhibited TGF??1?induced EndMT and the activation of the NF??B?Snail pathway. Transfection with a CSE plasmid significantly repressed TGF??1?induced expression of the mesenchymal marker and upregulated the expression of the endothelial marker, which was accompanied by the suppression of the NF??B?Snail pathway. The inhibitory effect of CSE overexpression on TGF??1?induced EndMT was significantly reversed by pretreatment with PAG. In conclusion, the current study provides novel information elucidating the beneficial effect of H2S on PAH through inhibiting the induction of the NF??B?Snail pathway and the subsequent process of EndMT in pulmonary arteries.

SUBMITTER: Zhang H

PROVIDER: S-EPMC6844600 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Protective effect of hydrogen sulfide on monocrotaline‑induced pulmonary arterial hypertension via inhibition of the endothelial mesenchymal transition.

Zhang Hui H Lin Yanjun Y Ma Yiwen Y Zhang Junfeng J Wang Changqian C Zhang Huili H

International journal of molecular medicine 20191001 6

Endothelial‑to‑mesenchymal transition (EndMT) serves an important role in the vascular remodeling of pulmonary arterial hypertension (PAH). However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in PAH and the process of EndMT. Male Sprague‑Dawley rats (10 weeks old) received a single dose of monocrotaline (MCT; i.p., 60 mg/kg) and were randomly treated with NaHS [an H2S donor; intraperitoneal (i.p.) 1 mg/kg/day], DL‑propagylglycine (an inhib ...[more]

PMID: 31573044

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Project description:Aims:The pathogenic mechanisms of pulmonary arterial hypertension (PAH) remain unclear, but involve dysfunctional endothelial cells (ECs), dysregulated immunity and inflammation in the lung. We hypothesize that a developmental process called endothelial to haematopoietic transition (EHT) contributes to the pathogenesis of pulmonary hypertension (PH). We sought to determine the role of EHT in mouse models of PH, to characterize specific cell types involved in this process, and to identify potential therapeutic targets to prevent disease progression. Methods and results:When transgenic mice with fluorescence protein ZsGreen-labelled ECs were treated with Sugen/hypoxia (Su/Hx) combination to induce PH, the percentage of ZsGreen+ haematopoietic cells in the peripheral blood, primarily of myeloid lineage, significantly increased. This occurrence coincided with the depletion of bone marrow (BM) ZsGreen+ c-kit+ CD45- endothelial progenitor cells (EPCs), which could be detected accumulating in the lung upon PH-induction. Quantitative RT-PCR based gene array analysis showed that key transcription factors driving haematopoiesis were expressed in these EPCs. When transplanted into lethally irradiated recipient mice, the BM-derived EPCs exhibited long-term engraftment and haematopoietic differentiation capability, indicating these EPCs are haemogenic in nature. Specific inhibition of the critical haematopoietic transcription factor Runx1 blocked the EHT process in vivo, prevented egress of the BM EPCs and ultimately attenuated PH progression in Su/Hx- as well as in monocrotaline-induced PH in mice. Thus, myeloid-skewed EHT promotes the development of PH and inhibition of this process prevents disease progression in mouse models of PH. Furthermore, high levels of Runx1 expression were found in circulating CD34+ CD133+ EPCs isolated from peripheral blood of patients with PH, supporting the clinical relevance of our proposed mechanism of EHT. Conclusion:EHT contributes to the pathogenesis of PAH. The transcription factor Runx1 may be a novel therapeutic target for the treatment of PAH.

Dataset Information

Protective effect of hydrogen sulfide on monocrotaline?induced pulmonary arterial hypertension via inhibition of the endothelial mesenchymal transition.

Publications

Protective effect of hydrogen sulfide on monocrotaline‑induced pulmonary arterial hypertension via inhibition of the endothelial mesenchymal transition.

Similar Datasets

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