Pressure stress delays cyclooxygenase-2 expression induced by interleukin-1β in cultured human pulmonary artery smooth muscle cells
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PROVIDER: S-EPMC10590958 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Project description:Electrical excitability, which plays an important role in excitation-contraction coupling in the pulmonary vasculature, is regulated by transmembrane ion flux in pulmonary artery smooth muscle cells (PASMC). This study aimed to characterize the electrophysiological properties and molecular identities of voltage-gated Na(+) channels in cultured human PASMC. We recorded tetrodotoxin (TTX) sensitive and rapidly inactivating Na(+) currents with properties similar to those described in cardiac myocytes. Using RT-PCR, we detected transcripts of seven Na(+) channel alpha genes (SCN2A, 3A, 4A, 7A, 8A, 9A, and 11A), and two beta subunit genes (SCN1B and 2B). Our results demonstrate that human PASMC express TTX-sensitive voltage-gated Na(+) channels. Their physiological functions remain unresolved, although our data suggest that Na(+) channel activity does not directly influence membrane potential, intracellular Ca(2+) release, or proliferation in normal human PASMC. Whether their expression and/or activity are heightened in the pathological state is discussed.
| S-EPMC1351366 | biostudies-literature
Project description:The chronic phase of pulmonary arterial hypertension (PAH) is associated with vascular remodeling, especially thickening of the smooth muscle layer of large pulmonary arteries and muscularization of small pulmonary vessels, which normally have no associated smooth muscle. Serotonin (5-hydroxytryptamine, 5-HT) has been shown to induce proliferation and hypertrophy of pulmonary artery smooth muscle cells (PASMC), and may be important for in vivo pulmonary vascular remodeling. Here, we show that 5-HT stimulates migration of pulmonary artery PASMC. Treatment with 5-HT for 16h increased migration of PASMC up to four-fold as monitored in a modified Boyden chamber assay. Increased migratory responses were associated with cellular morphological changes and reorganization of the actin cytoskeleton. 5-HT-induced alterations in morphology were previously shown in our laboratory to require cAMP [Lee SL, Fanburg BL. Serotonin produces a configurational change of cultured smooth muscle cells that is associated with elevation of intracellular cAMP. J Cell Phys 1992;150(2):396-405], and the 5-HT4 receptor was pharmacologically determined to be the primary activator of cAMP in bovine PASMC [Becker BN, Gettys TW, Middleton JP, Olsen CL, Albers FJ, Lee SL, et al. 8-Hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells. Mol Pharmacol 1992;42(5):817-25]. We examined the role of the 5-HT4 receptor and cAMP in 5-HT-induced bovine PASMC migration. PASMC express 5-HT4 receptor mRNA, and a 5-HT4 receptor antagonist and a cAMP antagonist completely blocked 5-HT-induced cellular migration. Consistent with our previous report that a cAMP-dependent Cl(-) channel is required for 5-HT-induced morphological changes in PASMC, phenylanthranilic acid, a Cl(-) channel blocker, inhibited actin cytoskeletal reorganization and migration produced by 5-HT. We conclude that 5-HT stimulates PASMC migration and associated cytoskeletal reorganization through the 5-HT4 receptor and cAMP activation of a chloride channel.
| S-EPMC1831537 | biostudies-literature
Project description:ObjectivesTo validate that dexlansoprazole, an anti-acid drug, can prevent pulmonary artery hypertension (PAH) in preclinical animal models and find the possible mechanism of action of dexlansoprazole for this new indication.MethodsThe efficacy of dexlansoprazole to attenuate PAH in vivo was evaluated in PAH animal models. Plasma guanosine 3', 5'-cyclic phosphate (cGMP) in PAH rats was measured by enzyme linked immunosorbent assay (ELISA). To investigate the anti-PAH effect of dexlansoprazole in vitro, proliferation and migration assays of primary cultured pulmonary artery smooth muscle cells (PASMCs) were performed. Furthermore, dexlansoprazole's function on fibroblast transition of vascular smooth muscle cells (VSMC) was explored by single cell ribonucleic acid (RNA) sequencing and RNAscope.ResultsDexlansoprazole could attenuate the pathologic process in monocrotaline (MCT)-, hypoxia-induced PAH rats and SU5416/hypoxia (SuHy)-induced PAH mice. The intervention with dexlansoprazole significantly inhibited elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular wall thickness. Furthermore, plasma cGMP in MCT-induced PAH rats was restored after receiving dexlansoprazole. In vitro, dexlansoprazole could inhibit PASMCs' proliferation and migration stimulated by platelet derived growth factor-BB (PDGF-BB). Moreover, dexlansoprazole significantly ameliorated pulmonary vascular remodeling by inhibiting VSMC phenotypic transition to fibroblast-like cells in a VSMC-specific multispectral lineage-tracing mouse.ConclusionsDexlansoprazole can prevent PAH through promoting cGMP generation and inhibiting pulmonary vascular remodeling through restraining PASMCs' proliferation, migration, and phenotypic transition to fibroblast-like cells. Consequently, PAH might be a new indication for dexlansoprazole.
| S-EPMC9452313 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-09-25 | GSE118363 | GEO
Project description:Pulmonary hypertension (PH) is one of the most devastating cardiovascular diseases worldwide and it draws much attention from numerous scientists. As an indispensable part of pulmonary artery, smooth muscle cells are worthy of being carefully investigated. To elucidate the pathogenesis of PH, several theories focusing on pulmonary artery smooth muscle cells (PASMC), such as hyperproliferation, resistance to apoptosis, and cancer theory, have been proposed and widely studied. Here, we tried to summarize the studies, concentrating on the role of PASMC in the development of PH, feasible molecular basis to intervene, and potential treatment to PH.
| S-EPMC7441461 | biostudies-literature
Project description:Pulmonary hypertension (PH) is a life‑threatening disease that often involves vascular remodeling. Although pulmonary arterial smooth muscle cells (PASMCs) are the primary participants in vascular remodeling, their biological role is not entirely clear. The present study analyzed the role of enhancer of zeste homolog 2 (EZH2) in vascular remodeling of PH by investigating the behavior of PASMCs. The expression levels of EZH2 in PASMCs in chronic thromboembolic pulmonary hypertension (CTEPH), a type of PH, were detected. The role of EZH2 in PASMC migration was investigated by wound‑healing assay following overexpression and knockdown. Functional enrichment analysis of the whole‑genome expression profiles of PASMCs with EZH2 overexpression was performed using an mRNA Human Gene Expression Microarray. Quantitative (q)PCR was performed to confirm the results of the microarray. EZH2 expression levels increased in CTEPH cell models. The overexpression of EZH2 enhanced PASMC migration compared with control conditions. Functional enrichment analysis of the differentially expressed genes following EZH2 overexpression indicated a strong link between EZH2 and the immune inflammatory response and oxidoreductase activity in PASMCs. mRNA expression levels of superoxide dismutase 3 were verified by qPCR. The results suggested that EZH2 was involved in the migration of PASMCs in PH, and may serve as a potential target for the treatment of PH.
| S-EPMC7751464 | biostudies-literature
Project description:Pulmonary Arterial Hypertension (PAH) is a progressive devastating disease characterized by excessive proliferation of the Pulmonary Arterial Smooth Muscle Cells (PASMCs). Studies suggest that PAH and cancers share an apoptosis-resistant state featuring excessive cell proliferation. MicroRNA-206 (miR-206) is known to regulate proliferation and is implicated in various types of cancers. However, the role of miR-206 in PAH has not been studied. In this study, it is hypothesized that miR-206 could play a role in the proliferation of PASMCs. In the present study, the expression patterns of miR-206 were investigated in normal and hypertensive mouse PASMCs. The effects of miR-206 in modulating cell proliferation, apoptosis and smooth muscle cell markers in human pulmonary artery smooth muscle cells (hPASMCs) were investigated in vitro. miR-206 expression in mouse PASMCs was correlated with an increase in right ventricular systolic pressure. Reduction of miR-206 levels in hPASMCs causes increased proliferation and reduced apoptosis and these effects were reversed by the overexpression of miR-206. miR-206 over expression also increased the levels of smooth muscle cell differentiation markers α-smooth muscle actin and calponin implicating its importance in the differentiation of SMCs. miR-206 overexpression down regulated Notch-3 expression, which is key a factor in PAH development. These results suggest that miR-206 is a potential regulator of proliferation, apoptosis and differentiation of PASMCs, and that it could be used as a novel treatment strategy in PAH.
| S-EPMC3468623 | biostudies-literature
Project description:AimsOrchestrating the transition from reversible medial hypertrophy to irreversible plexiform lesions is crucial for pulmonary arterial hypertension related to congenital heart disease (CHD-PAH). Transgelin is an actin-binding protein that modulates pulmonary arterial smooth muscle cell (PASMC) dysfunction. In this study, we aimed to probe the molecular mechanism and biological function of transgelin in the pathogenesis of CHD-PAH.Methods and resultsTransgelin expression was detected in lung tissues from both CHD-PAH patients and monocrotaline (MCT)-plus aortocaval (AV)-induced PAH rats by immunohistochemistry. In vitro, the effects of transgelin on the proliferation, migration, and apoptosis of human PASMCs (HPASMCs) were evaluated by the cell count and EdU assays, transwell migration assay, and TUNEL assay, respectively. And the effect of transgelin on the expression of HPASMC phenotype markers was assessed by the immunoblotting assay. (i) Compared with the normal control group (n = 12), transgelin expression was significantly overexpressed in the pulmonary arterioles of the reversible (n = 15) and irreversible CHD-PAH group (n = 4) (reversible group vs. control group: 18.2 ± 5.1 vs. 13.6 ± 2.6%, P < 0.05; irreversible group vs. control group: 29.9 ± 4.7 vs. 13.6 ± 2.6%, P < 0.001; irreversible group vs. reversible group: 29.9 ± 4.7 vs. 18.2 ± 5.1, P < 0.001). This result was further confirmed in MCT-AV-induced PAH rats. Besides, the transgelin expression level was positively correlated with the pathological grading of pulmonary arteries in CHD-PAH patients (r = 0.48, P = 0.03, n = 19). (ii) Compared with the normal control group (n = 12), TGF-β1 expression was notably overexpressed in the pulmonary arterioles of the reversible (n = 15) and irreversible CHD-PAH group (n = 4) (reversible group vs. control group: 14.8 ± 4.4 vs. 6.0 ± 2.5%, P < 0.001; irreversible group vs. control group: 20.1 ± 4.4 vs. 6.0 ± 2.5%, P < 0.001; irreversible group vs. reversible group: 20.1 ± 4.4 vs. 14.8 ± 4.4, P < 0.01). The progression-dependent correlation between TGF-β1 and transgelin was demonstrated in CHD-PAH patients (r = 0.48, P = 0.04, n = 19) and MCT-AV-induced PAH rats, which was further confirmed at sub-cellular levels. (iii) Knockdown of transgelin diminished proliferation, migration, apoptosis resistance, and phenotypic transformation of HPASMCs through repressing the TGF-β1 signalling pathway. On the contrary, transgelin overexpression resulted in the opposite effects.ConclusionsThese results indicate that transgelin may be an indicator of CHD-PAH development via boosting HPASMC dysfunction through positive regulation of the TGF-β1 signalling pathway, as well as a potential therapeutic target for the treatment of CHD-PAH.
| S-EPMC9715770 | biostudies-literature
Project description:BackgroundRecent clinical data suggest statins have transient but significant effects in patients with pulmonary arterial hypertension. In this study we explored the molecular effects of statins on distal human pulmonary artery smooth muscle cells (PASMCs) and their relevance to proliferation and apoptosis in pulmonary arterial hypertension.MethodsPrimary distal human PASMCs from patients and controls were treated with lipophilic (simvastatin, atorvastatin, mevastatin and fluvastatin), lipophobic (pravastatin) and nitric-oxide releasing statins and studied in terms of their DNA synthesis, proliferation, apoptosis, matrix metalloproteinase-9 and endothelin-1 release.ResultsTreatment of human PASMCs with selected statins inhibited DNA synthesis, proliferation and matrix metalloproteinase-9 production in a concentration-dependent manner. Statins differed in their effectiveness, the rank order of anti-mitogenic potency being simvastatin > atorvastatin > > pravastatin. Nevertheless, a novel nitric oxide-releasing derivative of pravastatin (NCX 6550) was effective. Lipophilic statins, such as simvastatin, also enhanced the anti-proliferative effects of iloprost and sildenafil, promoted apoptosis and inhibited the release of the mitogen and survival factor endothelin-1. These effects were reversed by mevalonate and the isoprenoid intermediate geranylgeranylpyrophosphate and were mimicked by inhibitors of the Rho and Rho-kinase.ConclusionsLipophilic statins exert direct effects on distal human PASMCs and are likely to involve inhibition of Rho GTPase signalling. These findings compliment some of the recently documented effects in patients with pulmonary arterial hypertension.
| S-EPMC3213146 | biostudies-literature
Project description:N-methyl-D-aspartate (NMDA) receptors are widely expressed in the central nervous system. However, their presence and function at extraneuronal sites is less well characterized. In the present study, we examined the expression of NMDA receptor subunit mRNA and protein in human pulmonary artery (HPA) by quantitative polymerase chain reaction (PCR), immunohistochemistry and immunoblotting. We demonstrate that both GluN1 and GluN2 subunit mRNAs are expressed in HPA. In addition, GluN1 and GluN2 (A-D) subunit proteins are expressed by human pulmonary artery smooth muscle cells (HPASMCs) in vitro and in vivo. These subunits localize on the surface of HPASMCs and form functional ion channels as evidenced by whole-cell patch-clamp electrophysiology and reduced phenylephrine-induced contractile responsiveness of human pulmonary artery by the NMDA receptor antagonist MK801 under hypoxic condition. HPASMCs also express high levels of serine racemase and vesicular glutamate transporter 1, suggesting a potential source of endogenous agonists for NMDA receptor activation. Our findings show HPASMCs express functional NMDA receptors in line with their effect on pulmonary vasoconstriction, and thereby suggest a novel therapeutic target for pharmacological modulations in settings associated with pulmonary vascular dysfunction.
| S-EPMC8050278 | biostudies-literature