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Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells.

ABSTRACT: Hypoxia-induced pulmonary vascular constriction and structure remodeling are the main causes of hypoxic pulmonary hypertension. In the present study, an adeno-associated virus vector, containing Tie2 promoter and hypoxia response elements, was designed and named HTSFcAng(1-7). Its targeting, hypoxic inducibility, and vascular relaxation were examined in vitro, and its therapeutic effects on hypobaric hypoxia-induced pulmonary hypertension were examined in rats. Transfection of HTSFcAng(1-7) specifically increased the expression of angiotensin-(1-7) in endothelial cells in normoxia. Hypoxia increased the expression of angiotensin-(1-7) in HTSFcAng(1-7)-transfected endothelial cells. The condition medium from HTSFcAng(1-7)-transfected endothelial cells inhibited the hypoxia-induced proliferation of pulmonary artery smooth muscle cells, relaxed the pulmonary artery rings, totally inhibited hypoxia-induced early contraction, enhanced maximum relaxation, and reversed phase II constriction to sustained relaxation. In hypoxic pulmonary hypertension rats, treatment with HTSFcAng(1-7) by nasal drip adeno-associated virus significantly reversed hypoxia-induced hemodynamic changes and pulmonary artery-wall remodeling, accompanied by the concomitant overexpression of angiotensin-(1-7), mainly in the endothelial cells in the lung. Therefore, hypoxia-inducible overexpression of angiotensin-(1-7) in pulmonary endothelial cells may be a potential strategy for the gene therapy of hypoxic pulmonary hypertension.

SUBMITTER: Liu ML

PROVIDER: S-EPMC7225382 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells.

Liu Man-Ling ML Xing Shu-Juan SJ Liang Xiao-Qing XQ Luo Ying Y Zhang Bo B Li Zhi-Chao ZC Dong Ming-Qing MQ

Molecular therapy. Methods & clinical development 20200418

Hypoxia-induced pulmonary vascular constriction and structure remodeling are the main causes of hypoxic pulmonary hypertension. In the present study, an adeno-associated virus vector, containing Tie2 promoter and hypoxia response elements, was designed and named HTSFcAng(1-7). Its targeting, hypoxic inducibility, and vascular relaxation were examined <i>in vitro</i>, and its therapeutic effects on hypobaric hypoxia-induced pulmonary hypertension were examined in rats. Transfection of HTSFcAng(1- ...[more]

PMID: 32426413

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Project description:BackgroundHypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension and characterized by pulmonary vascular remodeling and constriction. A large number of studies have shown that pulmonary vascular endothelial cells (PVECs) dysfunction plays an important role in the initiation and development stages of HPH, but the mechanism of PVECs dysfunction after hypoxia remains unclear. In this study, we explored the exact mechanism of PVECs dysfunction after hypoxia.MethodsIn vitro, we used primary cultured PVECs hypoxia model to mimic HPH injury. We detected the expressions of mitochondrial biogenesis markers, mitochondrial transcription factor A (TFAM) level inside mitochondria, mitochondrial quantity and function, and the components expressions of translocase of outer mitochondrial membrane (TOM) at 24 h after hypoxia. To explore the effects of Tom70 on mitochondrial biogenesis and functions of PVECs after hypoxia, Tom70 overexpression adenovirus was constructed, and the expressions of mitochondrial biogenesis markers, TFAM level inside mitochondria, mitochondrial quantity and function, and the functions of PVECs were detected. And in vivo, we used cre-dependent overexpression adenovirus of Tom70 in the Cdh5-CreERT2 mouse model of HPH to verify the role of upregulating PVECs Tom70 in improving HPH.ResultsHypoxia obviously increased the expressions of mitochondrial biogenesis markers for PGC-1α, NRF-1 and TFAM, but reduced the content of TFAM in mitochondria and the quantity and functions of mitochondria. In addition, only Tom70 expression among the TOM components was significantly decreased after hypoxia, and up-regulation of Tom70 significantly increased the content of TFAM in mitochondria of PVECs by transporting TFAM into mitochondria after hypoxia, enhanced the quantity and functions of mitochondria, improved the functions of PVECs, and ultimately alleviated HPH.ConclusionThe findings of present study demonstrated that hypoxia induced the decreased expression of Tom70 in PVECs, reduced the mitochondrial biogenesis-associated TFAM protein transporting into mitochondria, inhibited mitochondrial biogenesis, caused PVECs injury, and prompted the formation of HPH. However, up-regulation of Tom70 abolished the hypoxia-induced injurious effects on PVECs and alleviated HPH.

Project description:ObjectivesHIF2α is of vital importance in the regulation of endothelial dysfunction, cell proliferation, migration, and pulmonary vascular remodeling in pulmonary hypertension. Our previous studies demonstrated that conditional and inducible deletion of HIF2α in mouse lung endothelial cells, dramatically protected the mice against vascular remodeling and the development of pulmonary arterial hypertension (PAH). Here, we provide a novel transcriptome insight into the impact of HIF2α in PAH pathogenesis and the potential to use HIF2α-mediated gene sets to differentiate PAH human subjects.MethodsUsing transcriptome data, we first tapped the value of the difference in gene expression profile between wild type (WT) and Hif2a knockdown (KD) cell lines. We considered the deregulated genes between WT and Hif2a-KD cells as HIF2α influenced genes. By examining the lung tissue transcriptome data set with nine controls and eight PAH patients, we evaluated the HIF2α regulatory network in PAH pathogenesis to further determine the identification ability of HIF2α-mediated gene sets in human PAH subjects. On the other hand, using peripheral blood mononuclear cells (PBMCs) transcriptome data from PAH patients and healthy controls, we further validated the potential of the HIF2α-mediated PBMC gene sets as a possible diagnostic tool for PAH. To verify the ability of HIF2α-mediated gene sets for the identification of PAH, endothelial cell-specific Phd2 knockout mice with spontaneous pulmonary hypertension were used for reverse validation experiments.Results19 identified GO biological process terms were significantly correlated with the genes down-regulated in Hif2a-KD cells, all of which are strongly related to the PAH pathogenesis. We further assessed the discriminative power of these HIF2α-mediated gene sets in PAH human subjects. We found that the expression profile of the HIF2α-mediated gene sets in lung tissues and PBMCs were differentiated both between controls and PAH patients. Further, a significant positive correlation was observed between hypoxia and Phd2 deficiency mediated gene set expression profiles. As expected, 7 of the 19 significantly down-regulated GO terms in Hif2a-KD cells were found to overlap with the up-regulated GO gene sets in Phd2 EC-/- mice compared to WT controls, suggesting opposing effects of HIF2α and PHD2 on PAH pathogenesis.ConclusionHIF2α-mediated gene sets may be used to differentiate pulmonary arterial hypertension.

Dataset Information

Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells.

Publications

Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells.

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