Transdifferentiation of pulmonary arteriolar endothelial cells into smooth muscle‐like cells regulated by myocardin involved in hypoxia‐induced pulmonary vascular remodelling

Zhu, Pengcheng; Huang, Lei; Ge, Xin; Yan, Fei; Wu, Renliang; Ao, Qilin

doi:10.1111/j.1365-2613.2006.00503.x

Cited by 76 publications

(67 citation statements)

References 45 publications

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“…Wild-type or mutant 3 0 -UTRs of HIF-1a ( 29 We previously observed that prolonged exposure to hypoxia could lead to structural changes in small intrapulmonary arteries in rat lungs. 23 In this study, a time-dependent increase in neomuscularization and a thickening of small intrapulmonary arteries was observed, the neomuscularization was demonstrated by a-SMA immunohistochemical staining (Figure 1a). Muscularization of pulmonary arteries was fully established in the advanced stage of PH.…”

Section: Dual-luciferase Assaysmentioning

confidence: 95%

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MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1α/Fhl-1 pathway

Yue

Guan

Wang

et al. 2013

Laboratory Investigation

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Hypoxia-induced pulmonary hypertension (PH), which is characterized by vasoconstriction and subsequent structural remodeling of blood vessels, is an important event in chronic obstructive pulmonary disease patients and in people living at high altitudes. Hypoxia-inducible factor-1a (HIF-1a) and its regulator four-and-a-half LIM (Lin-11, Isl-1 and Mec-3) domain 1 (Fhl-1) have important roles in hypoxia-induced PH. is critical for myogenesis and related diseases; however, the role of miR-206 in hypoxia-induced PH is unknown. miR-206 expression was evaluated in a hypoxic rat model and in cultured hypoxic pulmonary artery smooth muscle cells (PASMCs) using real-time quantitative PCR (RT-qPCR). HIF-1a and Fhl-1 expression were evaluated using RT-qPCR, western blotting, immunohistochemistry and immunofluorescence. The function of miR-206 was assessed by transfecting miR-206 mimics and inhibitors. Dualluciferase reporter gene assays and western blotting were performed to validate the target genes of miR-206. siRNA targeted against Fhl-1 was used to investigate the effect of Fhl-1 on miR-206. Flow cytometry was used to detect the cell cycle phase distribution in each group of PASMCs. Significant downregulation of miR-206 in hypoxic lung tissue and PASMCs was identified, whereas HIF-1a and Fhl-1 were upregulated in these samples. The expression of miR-206 in the serum was different from that in the lung tissue. Transfection of pre-miR miR-206 in hypoxic conditions led to increased expression of HIF-1a and Fhl-1 rather than abolishing hypoxia-induced HIF-1a and Fhl-1, as was expected, and promoted the entry of cells into the S phase and enhanced PASMC proliferation. Fhl-1-targeted siRNA in PASMC prevented cell proliferation and led to an increased proportion of cells in the G1 phase without altering miR-206 expression. Bioinformatic analysis and dual-luciferase reporter gene assays revealed direct evidence for miR-206 targeting of HIF-1a. In conclusion, hypoxia-induced downregulation of miR-206 promotes PH by targeting the HIF-1a/Fhl-1 pathway in PASMCs. miR-206 could be a triggering factor of early stage of hypoxia-induced PH. Hypoxia-induced pulmonary hypertension (PH) is a serious disorder characterized by pulmonary vasoconstriction and enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) that lead to structural remodeling of blood vessel walls. PH is a common clinical manifestation of chronic obstructive pulmonary disease (COPD) and in people who live at high altitude. 1 Hypoxia-inducible factor-1a (HIF-1a) has a key role in the pathophysiology of hypoxia-induced PH.The four-and-a-half LIM domain 1 (Fhl-1) protein, a member of the Fhl family, has also been implicated in the biological pathways of muscle growth and differentiation in PH 2-4 and is regulated by HIF-1a in a feedback loop that serves to limit HIF-1a activity under conditions of prolonged hypoxia. 5 MicroRNAs (miRs) are a class of B23-nucleotide, noncoding single-stranded RNAs that regulate gene function by identifying the 3 0 -untransl...

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Section: Dual-luciferase Assaysmentioning

confidence: 95%

“…were exposed to normobaric hypoxia (FIO 2 of 0.10) in an isobaric hypoxic chamber 23 for 8 h per day for a period of 1, 4, 7, 14, 21 or 30 days (n ¼ 5 each). An oxygen analyzer (XP-3180; New Cosmos Electric, Osaka, Japan) was used to monitor oxygen content in the chamber.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1α/Fhl-1 pathway

Yue

Guan

Wang

et al. 2013

Laboratory Investigation

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“…In addition to the studies described above, there is evidence to suggest that EndMT may occur in many other disease settings, such as chronic pulmonary hypertension (Zhu et al, 2006;Arciniegas et al, 2007), atherosclerosis (Mironov et al, 1995), wound healing (Sarkisov et al, 1988;Lee and Kay, 2006), and in both acute and chronic kidney injury (Zeisberg et al, 2008). These emerging reports have characterised EndMT primarily in terms of marker expression, but have not addressed the precise molecular mechanisms of EndMT in disease.…”

Section: Endothelial-to-mesenchymal Transition In Cardiac Fibrosis Anmentioning

confidence: 99%

The role of endothelial-to-mesenchymal transition in cancer progression

2008

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Recent evidence has demonstrated that endothelial-to-mesenchymal transition (EndMT) may have a significant role in a number of diseases. Although EndMT has been previously studied as a critical process in heart development, it is now clear that EndMT can also occur postnatally in various pathologic settings, including cancer and cardiac fibrosis. During EndMT, resident endothelial cells delaminate from an organised cell layer and acquire a mesenchymal phenotype characterised by loss of cell–cell junctions, loss of endothelial markers, gain of mesenchymal markers, and acquisition of invasive and migratory properties. Endothelial-to-mesenchymal transition -derived cells are believed to function as fibroblasts in damaged tissue, and may therefore have an important role in tissue remodelling and fibrosis. In tumours, EndMT is an important source of cancer-associated fibroblasts (CAFs), which are known to facilitate tumour progression in several ways. These new findings suggest that targeting EndMT may be a novel therapeutic strategy, which is broadly applicable not only to cancer but also to various other disease states.

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“…So we tested the protein and mRNA expression of SUR2B and Kir6.1 in aortic and pulmonary arteries to investigate the possible mechanisms responsible for the regulation of vasorelaxation by H 2 S. H 2 S deficiency has been observed in animal models of systemic and pulmonary hypertension [16][17][18] . It also plays important roles in the pathogenesis of cardiovascular diseases [16][17][18][19][20][21][22][23][24] . The main mechanism for the cardiovascular actions of H 2 S was considered to be the activation of K ATP channels, because H 2 S increased whole-cell K ATP channel currents in rat aortic vascular smooth muscle cells [15] .…”

Section: Wwwchinapharcom Sun Y Et Almentioning

confidence: 99%

The vasorelaxing effect of hydrogen sulfide on isolated rat aortic rings versus pulmonary artery rings

et al. 2011

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Aim:To compare the vasorelaxing effects of hydrogen sulfide (H 2 S) on isolated aortic and pulmonary artery rings and to determine their action mechanisms. Methods: H 2 S-induced vasorelaxation of isolated rat aortic versus pulmonary artery rings under 95% O 2 and 5% CO 2 was analyzed. The expression of cystathinonine gamma-lyase (CSE), cystathionine beta synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3MST), SUR2B and Kir6.1 was examined. Results: NaHS caused vasorelaxation of rat aortic and pulmonary artery rings in a dose-dependent manner. NaHS dilated aortic rings to a greater extent (16.4%, 38.4%, 64.1%, 84.3%, and 95.9% at concentrations of 50, 100, 200, 500, and 1000 μmol/L, respectively) than pulmonary artery rings (10.1%, 22.2%, 50.6%, 73.6%, and 84.6% at concentrations of 50, 100, 200, 500 and 1000 μmol/L, respec tively). The EC 50 of the vasorelaxant effect for aortic rings was 152.17 μmol/L, whereas the EC 50 for pulmonary artery rings was 233.65 μmol/L. The vasorelaxing effect of H 2 S was markedly blocked b y cellular and mitochondrial membrane K ATP channel blockers in aortic rings (P<0.01). In contrast, only the cellular membrane K ATP channel blocker inhibited H 2 S-induced vasorelaxation in pulmonary artery rings. SUR2B mRNA and protein expression was higher in aortic rings than in pulmonary artery rings. Cystathinonine gamma-lyase (CSE) but not cystathionine beta synthase (CBS) expression in aortic rings was higher than in pulmonary artery rings. 3-Mercapto pyruvate sulfurtransferase (3MST) mRNA was lower in aortic rings than in pulmonary artery rings. Conclusion: The vasorelaxing effect of H 2 S on isolated aortic rings was more pronounced than the effect on pulmonary artery rings at specific concentrations, which might be associated with increased expression of the K ATP channel subunit SUR2B.

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Transdifferentiation of pulmonary arteriolar endothelial cells into smooth muscle‐like cells regulated by myocardin involved in hypoxia‐induced pulmonary vascular remodelling

Cited by 76 publications

References 45 publications

MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1α/Fhl-1 pathway

MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1α/Fhl-1 pathway

The role of endothelial-to-mesenchymal transition in cancer progression

The vasorelaxing effect of hydrogen sulfide on isolated rat aortic rings versus pulmonary artery rings

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