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Simple Summary: The lungs are key organs in mammals that shows adaptive changes in response to high altitude, and yaks (Bos grunniens) have adapted their lungs well to the hypoxic environment of Tibetan Plateau after a long period of evolution and natural selection. However, the long-term life of lowland cattle on the plateau can cause symptoms such as pulmonary arterial hypertension, wherein the abnormal proliferation of pulmonary vascular smooth muscle cells leads to the remodeling of the pulmonary vasculature, which is the main cause of pulmonary arterial hypertension. The underlying molecular mechanisms of lung adaptation to hypoxia in yaks remain largely unknown. In this study, we constructed stably transfected yak cell lines overexpressing PDK1 via lentiviral transfection, and we cultured yellow cattle and yak PASMCs, as well as PDK1-OEcon/OE, under normoxia and 10% O2 to explore the effects of hypoxia on the PDK1 and TGF-β/Smad signaling pathways in yak PASMCs. This will provide theoretical data at the cellular and molecular levels, along with basic information to further elucidate the mechanism of the PDK1-mediated TGF-β/Smad signaling pathway in yak PASMCs induced by hypoxia. The aim of this study was to investigate the effects of hypoxia-induced phenotype, glucose metabolism, ROS levels, and the PDK1-mediated regulation of TGF-β/Smad signaling in yellow cattles, yaks, and those overexpressing PDK1 PASMCs using growth curves, flow cytometry, scratch experiments, glucose and lactic acid assays, RT-qPCR, and Western blotting. The results showed that hypoxia significantly promoted proliferation, migration, antiapoptosis, ROS levels, glucose consumption, and lactate production in yellow cattle PASMCs (p < 0.05), and the cells were dedifferentiated from the contractile phenotype; conversely, hypoxia had no significant effect on yak PASMCs (p > 0.05). PDK1 overexpression significantly promoted proliferation, antiapoptosis, glucose consumption, and lactate production in yak PASMCs under normoxia and hypoxia (p < 0.05), decreased their migration levels under hypoxia (p < 0.05), and dedifferentiated the contractile phenotype of the cells. Overexpression of PDK1 in yak PASMCs is detrimental to their adaptation to hypoxic environments. Yak PASMCs adapted to the effects of hypoxia on lung tissue by downregulating the expression of genes related to the PDK1 and TGF-β/Smad signaling pathways. Taken together, the regulation of PDK1-mediated TGF-β/Smad signaling may be involved in the process of yaks' adaptation to the hypoxic environment of the plateau, reflecting the good adaptive ability of yaks. The present study provides basic information to further elucidate the mechanism of PDK1-mediated TGF-β/Smad signaling induced by hypoxia in the lungs of yaks, as well as target genes for the treatment of plateau diseases in humans and animals. [ABSTRACT FROM AUTHOR]

Objective: To explore the role of interleukin (IL)‐17 in connective tissue disease‐associated pulmonary arterial hypertension (CTD‐PAH) and to investigate its possible mechanism on pulmonary artery smooth muscle cells (PASMCs). Methods: Enzyme‐linked immunosorbent assay (ELISA) were used to compare levels of serum IL‐17 in patients with CTD‐PAH and healthy controls (HCs). After treatment for 3 months, the serum IL‐17 levels were tested in CTD‐PAH. ELISA and immunohistochemistry were used to compare levels of serum IL‐17 and numbers of pulmonary artery IL‐17+ cells, respectively, in a rat model of monocrotaline‐induced PAH and untreated rats. Proliferation, migration, and inflammatory factors expression of PASMCs were assessed after stimulation with different concentrations of IL‐17 for various time periods. Proteins in the mitogen‐activated protein kinase (MAPK) pathway were examined by western blot. Results: Levels of IL‐17 were upregulated in patients with CTD‐PAH compared to HCs. After 3 months of treatment, serum IL‐17 levels were downregulated with pulmonary artery pressure amelioration. Moreover, serum IL‐17 levels and numbers of IL‐17+ cells infiltrating lung arterioles were increased in PAH model rats. IL‐17 could dose‐ and time‐dependently promote proliferation and migration of PASMCs as well as time‐dependently induce IL‐6 and intercellular cell adhesion molecule‐1 (ICAM‐1) expression. The levels of MKK6 increased after IL‐17 treatment. Inhibition of MAPK decreased proliferation of PASMCs. Conclusion: Levels of IL‐17 may increase in CTD‐PAH, and IL‐17 promotes proliferation, migration, and secretion of IL‐6 and ICAM in PASMCs, respectively, which likely involves the p‐38 MAPK pathway. [ABSTRACT FROM AUTHOR]

Background Uncontrolled proliferation of pulmonary artery smooth muscle cells (PASMCs) contributes to the pathogenesis of pulmonary arterial hypertension (PAH). In this work, we defined the precise part of circ_0068481 in PASMC proliferation and migration induced by hypoxia. We hypothesized that circ_0068481 enhanced hypoxia-induced PASMC proliferation, invasion, and migration through the microRNA (miR)-361-3p/Krüppel-like factor 5 (KLF5) pathway. Methods Human PASMCs (hPASMCs) were exposed to hypoxic (3% O2) conditions. Circ_0068481, miR-361-3p, and KLF5 levels were gauged by qRT-PCR and western blot. Cell viability, proliferation, invasion, and migration were detected by XTT, EdU incorporation, transwell, and wound-healing assays, respectively. Dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays were performed to confirm the direct relationship between miR-361-3p and circ_0068481 or KLF5. Results Circ_0068481 expression was increased in the serum of PAH patients and hypoxia-induced hPASMCs. Downregulation of circ_0068481 attenuated hypoxia-induced promotion in hPASMC proliferation, invasion, and migration. Circ_0068481 directly targeted miR-361-3p, and miR-361-3p downregulation reversed the inhibitory effects of circ_0068481 silencing on hypoxia-induced hPASMC proliferation, invasion, and migration. KLF5 was a direct miR-361-3p target, and miR-361-3p upregulation mitigated hypoxia-induced hPASMC proliferation, invasion, and migration by inhibiting KLF5 expression. Moreover, circ_0068481-induced KLF5 expression by binding to miR-361-3p in hypoxic hPASMCs. Conclusions Circ_0068481 knockdown ameliorated hypoxia-induced hPASMC proliferation, invasion, and migration at least in part through the miR-361-3p/KLF5 axis. [ABSTRACT FROM AUTHOR]

Abstract Aims Orchestrating 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 results Transgelin 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

Aims: Orchestrating 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 results: Transgelin 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. Conclusions: These 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. [ABSTRACT FROM AUTHOR]

[Display omitted] Hypoxic pulmonary hypertension (HPH) is a serious and life-threatening chronic cardiopulmonary disease characterized by progressive elevation of pulmonary artery pressure and pulmonary vascular remodeling. Mesenchymal stem cell- derived exosomes (MSC-Exos) can relieve HPH by reversing pulmonary vascular remodeling. The HPH model was established in healthy male Sprague-Dawley (SD) rats aged 6 to 8 weeks. The rats were placed in a room with oxygen concentration of (10 ± 1) % for 8 hours a day over 28 days, were then injected intravenously with MSC-Exos (100 ug protein/kg) or equal-volume phosphate buffer saline (PBS) once a day over 1 week. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI) and pulmonary vascular remodeling were observed after anesthesia. In addition, platelet-derived growth factor BB (PDGF-BB) was used to stimulate rat pulmonary artery smooth muscle cells (PASMCs) to construct HPH pathological cell models. The results showed that MSC-Exos could not only reduce the elevation of RVSP, right ventricular hypertrophy and the degree of pulmonary vascular remodeling in HPH rats, but also reduce the proliferation, migration and apoptosis resistance of PASMCs. Finally, GSE53408 and GSE113439 datasets were analyzed and showed that the expression of Hsp90aa1 and pERK/ERK were significantly increased in HPH, also could be inhibited by MSC-Exos. Meanwhile, inhibition of Hsp90aa1 also reduced PASMCs migration and pERK/ERK protein level. In conclusion, MSC-Exos alleviated HPH by suppressing PASMCs proliferation, migration and apoptosis resistance through inhibiting the Hsp90aa1/ERK/pERK pathway. [ABSTRACT FROM AUTHOR]

Abstract Background In this study, we aimed to investigate whether and how lncRNA CASC2 was involved in hypoxia-induced pulmonary hypertension (PH)-related vascular remodeling. Methods The expression of lncRNAs or mRNAs was detected by qRT-PCR, and western blot analysis or immunochemistry was employed for detecting the protein expression. Cell number assay and EdU (5-ethynyl-2′-deoxyuridine) staining were performed to assess cell proliferation. Besides, flow cytometry and wound healing assay were employed for assessments of cell apoptosis and cell migration, respectively. Rat model of hypoxic PH was established and the hemodynamic measurements were performed. Hematoxylin and eosin (HE) and Masson′s trichrome staining were carried out for pulmonary artery morphometric analysis. Results The expression of lncRNA CASC2 was decreased in hypoxia-induced rat pulmonary arterial tissues and pulmonary artery smooth muscle cells (PASMCs). Up-regulation of lncRNA CASC2 inhibited cell proliferation, migration yet enhanced apoptosis in vitro and in vivo in hypoxia-induced PH. Western blot analysis and immunochemistry showed that up-regulation of lncRNA CASC2 greatly decreased the expression of phenotype switch-related marker α-SMA in hypoxia-induced PH. Furthermore, it was indicated by the pulmonary artery morphometric analysis that lncRNA CASC2 suppressed vascular remodeling of hypoxia-induced rat pulmonary arterial tissues. Conclusion LncRNA CASC2 inhibited cell proliferation, migration and phenotypic switch of PASMCs to inhibit the vascular remodeling in hypoxia-induced PH.

Pulmonary vascular remodeling (PVR) is not only the main pathophysiological feature of Pulmonary Artery Hypertension (PAH) but also the main reason for the progressive aggravation of PAH. Its central link is the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs), which leads to the imbalance of proliferation/apoptosis, leads to the formation of PAH. At present, we found that hypoxia can up-regulate the expression of mitophagy protein PINK1/Parkin, induce the proliferation of PASMCs, and inhibit apoptosis. Knocking down PINK1−/− and/or Parkin−/-, found that the proliferation of PASMCs was significantly inhibited compared with that of PINK1/Parkin, while the proliferation of cells under PINK1−/− Parkin−/- was significantly lower than that of PINK1−/− Parkin+/+or PINK1+/+ Parkin−/-. These results suggest that hypoxia can activate the PINK1/Parkin-mediated mitophagy pathway, induce the excessive proliferation of PASMCs, eventually lead to PVR, leading to HPH. Our team is further exploring which substances in HPH can induce mitotic response, which molecules specifically mediate the activation of mitotic pathways, and what role they play in the occurrence and development of HPH disease. • PVR is the main pathophysiological feature of HPH, which leads to the occurrence and progression of HPH. • Hypoxia can cause excessive proliferation of PASMCs, induce the formation of PVR, and eventually lead to the occurrence of HPH. • Hypoxia regulates the proliferation of PASMCs through mitophagy mediated by PINK1/Parkin, and apoptosis is blocked. [ABSTRACT FROM AUTHOR]

• A complete description of the structure and functions of the Transmembrane protein 16A (TMEM16A). • An objective statement of the role of TMEM16A in pulmonary hypertension, the mechanism of action and the controversy. • An innovative presentation of the latest research on TMEM16A in pulmonary hypertension, hypertension and portal hypertension, with intercomparisons. Transmembrane protein 16A (TMEM16A), a member of the TMEM16 family, is the molecular basis of Ca2+-activated chloride channels (CaCCs) and is involved in a variety of physiological and pathological processes. Previous studies have focused more on respiratory-related diseases and tumors. However, recent studies have identified an important role for TMEM16A in cardiovascular diseases, especially in pulmonary hypertension. TMEM16A is expressed in both pulmonary artery smooth muscle cells and pulmonary artery endothelial cells and is involved in the development of pulmonary hypertension. This paper presents the structure and function of TMEM16A, the pathogenesis of pulmonary hypertension, and highlights the role and mechanism of TMEM16A in pulmonary hypertension, summarizing the controversies in this field and taking into account hypertension and portal hypertension, which have similar pathogenesis. It is hoped that the unique role of TMEM16A in pulmonary hypertension will be illustrated and provide ideas for research in this area. [ABSTRACT FROM AUTHOR]

Activation of AMP-activated protein kinase (AMPK) plays an important role in cardiovascular protection. It can inhibit arterial smooth muscle cell proliferation and cardiac fibroblast collagen synthesis induced by anoxia. However, the role of AMPK-dependent signalling cascades in the pulmonary vascular system is currently unknown. This study aims to determine the effects of AMPK on pulmonary hypertension and pulmonary vessel remodelling induced by hypoxia in rats using in vivo and in vitro studies. In vivo study: pulmonary hypertension, right ventricular hypertrophy and pulmonary vascular remodelling were found in hypoxic rats. Meanwhile, AMPKα and phosphorylated AMPKα were increased markedly in pulmonary arterioles and lung tissues. Mean pulmonary arterial pressure, index of right ventricular hypertrophy and parameters of pulmonary vascular remodelling, including vessel wall area/total area, density of nuclei in medial smooth muscle cells, and thickness of the medial smooth muscle cell layer were markedly suppressed by AICAR, an AMPK agonist. In vitro study: the expression of AMPKα and phosphorylated AMPKα was increased in pulmonary artery smooth muscle cells (PASMCs) under hypoxic conditions. The effects of PASMC proliferation stimulated by hypoxia were reinforced by treatment with Compound C, an AMPK inhibitor. AICAR inhibited the proliferation of PASMCs stimulated by hypoxia. These findings suggest that AMPK is involved in the formation of hypoxia-induced pulmonary hypertension and pulmonary vessel remodelling. Up-regulating AMPK can contribute to decreasing pulmonary vessel remodelling and pulmonary hypertension induced by hypoxia. [ABSTRACT FROM AUTHOR]

Abstract: Pulmonary arterial hypertension (PAH) is a complex and multifactorial disease characterized by vascular remodeling, vasoconstriction, inflammation and thrombosis. Although the available therapies have resulted in improvements in morbidity and survival, PAH remains a severe and devastating disease with a poor prognosis and a high mortality, justifying the need of novel therapeutic targets. An increasing number of studies have demonstrated that endothelial cells (ECs), smooth muscle cells (SMCs) and fibroblasts of the pulmonary vessel wall, as well as platelets and inflammatory cells have a role in PAH pathogenesis. This review aims to integrate the interplay among different types of cells, during PAH development and progression, and the impact of current therapies in cellular modulation. The interplay among endothelial cells, smooth muscle cells and fibroblasts present in pulmonary vessels wall, platelets and inflammatory cells is regulated by several mediators produced by these cells, contributing to the pathophysiologic features of PAH. Current therapies are mainly focused in the pulmonary vascular tone and in the endothelial dysfunction. However, once they have not been effective, novel therapies targeting other PAH features, such as inflammation and platelet dysfunction are emerging. Further understanding of the interplay among different vascular cell types involved in PAH development and progression can contribute to find novel therapeutic targets, decreasing PAH mortality and morbidity in the future. [Copyright &y& Elsevier]

Abstract: G protein-coupled receptors (GPCRs) represent the largest family of transmembrane receptors and are prime therapeutic targets. The odorant and taste receptors account for over half of the GPCR repertoire, yet they are generally excluded from large-scale, drug candidate analyses. Accumulating molecular evidence indicates that the odorant and taste receptors are widely expressed throughout the body and functional beyond the oronasal cavity — with roles including nutrient sensing, autophagy, muscle regeneration, regulation of gut motility, protective airway reflexes, bronchodilation, and respiratory disease. Given this expanding array of actions, the restricted perception of these GPCRs as mere mediators of smell and taste is outdated. Moreover, delineation of the precise actions of odorant and taste GPCRs continues to be hampered by the relative paucity of selective and specific experimental tools, as well as the lack of defined receptor pharmacology. In this review, we summarize the evidence for expression and function of odorant and taste receptors in tissues beyond the nose and mouth, and we highlight their broad potential in physiology and pathophysiology. [Copyright &y& Elsevier]

Abstract: Pulmonary arterial hypertension (PAH) is a progressive condition in which remodeling of the pulmonary vasculature plays an important role. The vascular remodeling involves pulmonary arterial smooth muscle cell (PASMC) proliferation and apoptosis, which is affected by several arachidonic acid metabolites. 15-oxo-Eicosatetraenoic acid (15-oxo-ETE) is one of the metabolites. However, the biological role of 15-oxo-ETE in PASMCs remains unknown. Here we show evidence for the modulation of PASMC apoptosis by 15-oxo-ETE. We found that 15-oxo-ETE increased rat and human PASMC viability. Consistently, 15-oxo-ETE attenuated nuclear fragmentation and DNA strand breaks, decreased caspase-3 activity, reduced mitochondrial depolarization, and increased Bcl-2 expression. Interestingly, the anti-apoptotic effect of 15-oxo-ETE was lost when the Akt intracellular signaling pathway was blocked. Taken together, we have established that 15-oxo-ETE protects PASMCs against apoptosis through the Akt pathway. These results suggest that 15-oxo-ETE seems to be a potential agent for PAH controls by preventing unwanted PASMC death. [Copyright &y& Elsevier]

Hypoxia-inducible factor-1 (HIF-1) regulates the expression of hypoxia-inducible genes by binding erythropoietin (EPO) enhancer fragments. Of these genes, HIF-1 upregulates voltage-gated K+1.2 channels (Kv1.2) in rat PC12 cells. Whether HIF-1 regulates hypoxia-induced Kv channel expression in cultured pulmonary artery smooth muscle cells (PASMCs), however, has not been determined. In this study, we investigated the effects of hypoxia on the expression of Kv1.2 Kv1.5, Kv2.1, and Kv9.3 channels in PASMCs and examined the direct role of HIF-1 by transfecting either wild type or mutant EPO enhancer fragments. Our results showed that 18 h exposure to hypoxia significantly increased the expression of Kv1.2, Kv1.5, Kv2.1, and Kv9.3; and this hypoxia-induced upregulation was completely inhibited after transfection with the wild type but not mutant EPO enhancer fragment. These results indicate that HIF-1 regulates hypoxia-stimulated induction of Kv1.2, Kv1.5, Kv2.1, and Kv9.3 channels in cultured PASMCs.

Abstract: As we uncover the complex pathophysiology underlying idiopathic and familial pulmonary arterial hypertension, multiple disease associated pathways, cell types and processes reveal links to elements of the serotonin system. Beyond the original ‘serotonin hypothesis’ observed with anorexigens, and the latterly demonstrated association with vascular tone and pulmonary artery smooth muscle cell proliferation, recent studies suggest links to BMPR2, PDGF and RhoK pathways, as well as an impact upon more complex lesion formation and pathologic bone marrow progenitor mobilization. Clinical experience with antagonists targeting the various elements of the serotonin pathway has been unsatisfactory, yet perhaps this is less than surprising given our expanding knowledge around serotonin production and signaling biology, which indicate opportunities for novel therapeutic options. [Copyright &y& Elsevier]

Objective: Clinically, the effect of chronic hypoxia (CH) in the pulmonary circulation alternates between phases of pulmonary artery hypertension (CH-PAHT) and normoxic normotensive remission (N-RE). Little information is available on the role of calcium-sensitive potassium channels (BKCa) in both CH-PAHT and N-RE phases. In the present study, we investigated the effects of both CH and N-RE on BKCa channels activity and their consequences on hypoxic pulmonary vasoconstriction (HPV). Methods: Using isolated ring preparation, the patch-clamp technique, RT-PCR and Western immunoblotting, we examined the role of the BKCa channel in normoxic, CH-PAHT and N-RE rat pulmonary artery smooth muscle cells (PASMCs). Results: In intrapulmonary arterial rings, acute hypoxia induced contraction in control vessels, relaxation in the N-RE rats, and had no effect in CH-PAHT. The hypoxia-induced relaxation in the N-RE rat pulmonary arteries was abolished by iberiotoxin (IbTx), a specific BKCa blocker. The IbTx-sensitive whole-cell KCa channel current was reduced in CH-PAHT and increased in N-RE rat PASMCs. The BKCa channel conductance and voltage sensitivity were not altered in CH and N-RE rat PASMCs, whereas its calcium sensitivity was decreased and increased in CH and N-RE rat PASMCs, respectively. Results of RT-PCR and Western blot analysis revealed a decrease in the mRNA and protein of the BKCa α-subunit in CH, whereas no change at protein level was observed in the N-RE. Conclusion: In rat PASMCs, CH and N-RE are associated with a down- and up-regulation of BKCa activity, respectively, mainly due to modifications of its Ca2+ sensitivity. This could explain the acute hypoxic pulmonary constriction and relaxation observed in CH and N-RE rats, respectively. [Copyright &y& Elsevier]

Pulmonary arterial hypertension (PAH), a chronic and progressive disease of the lung vascular system, is characterized by vasculopathy in the pulmonary arterioles, especially in endothelial cells and pulmonary vascular smooth cells. Several mechanisms are involved in PAH occurrence and development, and all are characterized by excessive pulmonary vasoconstriction and abnormal vascular remodeling, which leads to a progressive resistance to blood flow and an increase in pulmonary artery pressure. Recent studies have shown that endoplasmic reticulum (ER) stress is implicated in the pathophysiology of PAH. In this review, we highlight the effect of ER stress on the proliferation and apoptosis of endothelial cells and pulmonary vascular smooth muscle cells, and discuss the feasibility of targeting unfolded protein response components as a strategy to reverse or alleviate the progression of PAH., Competing Interests: None., (AJTR Copyright © 2020.)

Background: In this study, we aimed to investigate whether and how lncRNA CASC2 was involved in hypoxia-induced pulmonary hypertension (PH)-related vascular remodeling.Methods: The expression of lncRNAs or mRNAs was detected by qRT-PCR, and western blot analysis or immunochemistry was employed for detecting the protein expression. Cell number assay and EdU (5-ethynyl-2'-deoxyuridine) staining were performed to assess cell proliferation. Besides, flow cytometry and wound healing assay were employed for assessments of cell apoptosis and cell migration, respectively. Rat model of hypoxic PH was established and the hemodynamic measurements were performed. Hematoxylin and eosin (HE) and Masson's trichrome staining were carried out for pulmonary artery morphometric analysis.Results: The expression of lncRNA CASC2 was decreased in hypoxia-induced rat pulmonary arterial tissues and pulmonary artery smooth muscle cells (PASMCs). Up-regulation of lncRNA CASC2 inhibited cell proliferation, migration yet enhanced apoptosis in vitro and in vivo in hypoxia-induced PH. Western blot analysis and immunochemistry showed that up-regulation of lncRNA CASC2 greatly decreased the expression of phenotype switch-related marker α-SMA in hypoxia-induced PH. Furthermore, it was indicated by the pulmonary artery morphometric analysis that lncRNA CASC2 suppressed vascular remodeling of hypoxia-induced rat pulmonary arterial tissues.Conclusion: LncRNA CASC2 inhibited cell proliferation, migration and phenotypic switch of PASMCs to inhibit the vascular remodeling in hypoxia-induced PH. [ABSTRACT FROM AUTHOR]