scholarly journals QKI Promotes Hypoxia Induced Smooth Muscle Reprogramming in Pulmonary Hypertension

2021 ◽  
Author(s):  
Huijie Huang ◽  
Donghai Lin ◽  
Li Hu ◽  
Jie Wang ◽  
Yanfang Yu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Biological Significance ◽  
Pulmonary Vascular Remodeling ◽  
Mrna Stabilization ◽  
Elevated Protein ◽  
Phenotypic Transformation

Abstract Background: Pulmonary hypertension (PH) is a complex and progressive cardiopulmonary disorder with poor prognosis and limited therapeutic treatments. Recent evidence suggests that RNA binding proteins (RBPs) participate in the pathogenesis of human and experimental pulmonary arterial hypertension. Quaking (QKI) as an important RBPs is involved in mRNA biogenesis, export, decay and translation. However, the biological significance of QKI in phenotypic transformation of PASMCs in PH as well as in abnormal pulmonary vascular remodeling remain elusive. Methods: We assessed the expression pattern, phenotypic transformation effect, and mechanism of QKI in rodent Su/Hx-induced PH model, Human PAH samples and in HPASMCs.Results: Elevated protein expression level of QKI was found in animal PH and human PAH samples, thus in hypoxic HPASMCs. Inhibition of QKI attenuated proliferation and phenotype switching in HPASMCs. Mechanistically, QKI was found to mediate STAT3 mRNA stabilization by binding to its 3’Untranslated Region (3’-UTR). Downregulation of QKI attenuated STAT3 expression in PASMCs, while overexpression of STAT3 in PASMCs was widely regarded to be involved in the progression of PH. In addition, as a transcription factor, STAT3 was identified to bound to miR-146b promoter to induce its expression, while miR-146b was proved to promote smooth muscle reprogramming through inhibiting STAT1 and TET2 expression during pulmonary vascular remodeling.Conclusions: Our study demonstrates the QKI-STAT3-miR-146b pathway as a novel mechanistic insights into hypoxic reprogramming that permits vascular remodeling, and thus provides proof of concept for anti-remodeling therapy through the direct modulation this axis in PH.

scholarly journals Pulmonary Artery Smooth Muscle Cell Senescence Promotes the Proliferation of PASMCs by Paracrine IL-6 in Hypoxia-Induced Pulmonary Hypertension

2021 ◽  
Vol 12 ◽  
Author(s):  
Ai-Ping Wang ◽  
Fang Yang ◽  
Ying Tian ◽  
Jian-Hui Su ◽  
Qing Gu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Remodeling ◽  
Pathophysiological Mechanism ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Artery Smooth Muscle ◽  
Active Substances

Pulmonary hypertension (PH) is a critical and dangerous disease in cardiovascular system. Pulmonary vascular remodeling is an important pathophysiological mechanism for the development of pulmonary arterial hypertension. Pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy, and enhancing secretory activity are the main causes of pulmonary vascular remodeling. Previous studies have proven that various active substances and inflammatory factors, such as interleukin 6 (IL-6), IL-8, chemotactic factor for monocyte 1, etc., are involved in pulmonary vascular remodeling in PH. However, the underlying mechanisms of these active substances to promote the PASMC proliferation remain to be elucidated. In our study, we demonstrated that PASMC senescence, as a physiopathologic mechanism, played an essential role in hypoxia-induced PASMC proliferation. In the progression of PH, senescence PASMCs could contribute to PASMC proliferation via increasing the expression of paracrine IL-6 (senescence-associated secretory phenotype). In addition, we found that activated mTOR/S6K1 pathway can promote PASMC senescence and elevate hypoxia-induced PASMC proliferation. Further study revealed that the activation of mTOR/S6K1 pathway was responsible for senescence PASMCs inducing PASMC proliferation via paracrine IL-6. Targeted inhibition of PASMC senescence could effectively suppress PASMC proliferation and relieve pulmonary vascular remodeling in PH, indicating a potential for the exploration of novel anti-PH strategies.

scholarly journals Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension

2015 ◽  
Vol 308 (2) ◽  
pp. L208-L220 ◽  
Author(s):  
Haiyang Tang ◽  
Jiwang Chen ◽  
Dustin R. Fraidenburg ◽  
Shanshan Song ◽  
Justin R. Sysol ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Pulmonary Vascular Remodeling ◽  
Akt Isoforms ◽  
Cell Proliferation And Migration ◽  
Pulmonary Arterial ◽  
And Migration ◽  
Proliferation And Migration

Pulmonary vascular remodeling, mainly attributable to enhanced pulmonary arterial smooth muscle cell proliferation and migration, is a major cause for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary hypertension. The signaling cascade through Akt, comprised of three isoforms (Akt1–3) with distinct but overlapping functions, is involved in regulating cell proliferation and migration. This study aims to investigate whether the Akt/mammalian target of rapamycin (mTOR) pathway, and particularly which Akt isoform, contributes to the development and progression of pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Compared with the wild-type littermates, Akt1 −/− mice were protected against the development and progression of chronic HPH, whereas Akt2 −/− mice did not demonstrate any significant protection against the development of HPH. Furthermore, pulmonary vascular remodeling was significantly attenuated in the Akt1 −/− mice, with no significant effect noted in the Akt2 −/− mice after chronic exposure to normobaric hypoxia (10% O2). Overexpression of the upstream repressor of Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and conditional and inducible knockout of mTOR in smooth muscle cells were also shown to attenuate the rise in right ventricular systolic pressure and the development of right ventricular hypertrophy. In conclusion, Akt isoforms appear to have a unique function within the pulmonary vasculature, with the Akt1 isoform having a dominant role in pulmonary vascular remodeling associated with HPH. The PTEN/Akt1/mTOR signaling pathway will continue to be a critical area of study in the pathogenesis of pulmonary hypertension, and specific Akt isoforms may help specify therapeutic targets for the treatment of pulmonary hypertension.

scholarly journals Eplerenone Improves Pulmonary Vascular Remodeling and Hypertension by Inhibition of the Mineralocorticoid Receptor in Endothelial Cells

Hypertension ◽  
2021 ◽  
Author(s):  
Jessica Kowalski ◽  
Lisa Deng ◽  
Chiara Suennen ◽  
Duygu Koca ◽  
David Meral ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Mineralocorticoid Receptor ◽  
Chronic Hypoxia ◽  
Cell Type ◽  
Pulmonary Vascular Remodeling ◽  
Cell Type Specific

Pulmonary hypertension is characterized by progressive remodeling of the pulmonary arteries, however, this is not therapeutically targeted yet. Aldosterone and the MR (mineralocorticoid receptor) are key drivers of cardiovascular disease, and there is a growing body of evidence suggesting a role in pulmonary hypertension. Thus, the aim of this study was to investigate the impact of cell type-specific deletion of MR on pulmonary vascular remodeling. To induce pulmonary hypertension, mice were exposed to chronic hypoxia for 6 weeks. Treatment with the MR antagonist eplerenone attenuated pulmonary vascular remodeling, hypertension, and right ventricular dysfunction. In contrast, aldosterone infusion via osmotic minipumps induced pulmonary vascular remodeling. We created 4 different mouse models with cell type-specific MR deletion in smooth muscle cells, endothelial cells, macrophages, or fibroblasts and exposed them to chronic hypoxia. MR deletion from endothelial cells fully recapitulated the beneficial effects of eplerenone while MR deletion from other cell types had no detectable effect on pulmonary vascular remodeling. RNA-seq from isolated MR-deficient and wildtype pulmonary endothelial cells revealed differentially expressed genes as potential downstream mediators of MR related to pulmonary hypertension, including genes related to the endothelin signaling pathway. MR antagonists improve hypoxia-induced pulmonary vascular remodeling via inhibition of MR in endothelial cells but independent from MR in smooth muscle cells, fibroblasts, or macrophages. The results from this study provide the basis for future investigation of potential downstream mediators of MR involved in pulmonary hypertension and further support the clinical evaluation of MR antagonists in pulmonary hypertension.

P4146The six-transmembrane protein Stamp2 protects from hypoxia-induced pulmonary vascular remodeling and pulmonary hypertension via actions in mononuclear cells and CXCL12

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Batool ◽  
E M Berghausen ◽  
M Zierden ◽  
M Vantler ◽  
S Baldus ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Transmembrane Protein ◽  
Muscle Cells ◽  
Brdu Incorporation ◽  
Vascular Remodelling ◽  
Pulmonary Vascular Remodeling

Abstract Background The six-transmembrane protein of prostate (Stamp2) is a potent anti-inflammatory player in adipocytes and also in macrophages. Stamp2's actions in these cells protects from diet-induced diabetes and from atherosclerosis mice. As chronic inflammation is a hallmark of pulmonary arterial hypertension (PH), we sought to investigate the role of Stamp2 in PH. Methods and results Morphometric analyses of small pulmonary arteries after 3 weeks of chronic hypoxia (10% O2) showed aggravated pulmonary vascular remodeling in Stamp2−/− mice as compared to WT, demonstrated by a significantly reduced number of non-muscularized vessels and higher extent of fully-muscularized vessels. Consequently, right ventricular systolic pressure (RVSP, Millar catheter via right jugular vein) was significantly higher in Stamp2−/− mice (33.4±0.7 mmHg vs. 30.3±1.4, p<0.05). As endothelial (EC) and smooth muscle cells (PASMC) are critical for remodeling processes in PH, the role of Stamp2 in these cells was explored. However, siRNA-mediated knock-down of Stamp2 in human microvascular EC had no effect on apoptotic susceptibility (CellDeath Detection ELISA), or release of IL-6 (qPCR). Furthermore, Stamp2-deficiency in isolated primary PASMC had no effect on proliferation (BrdU incorporation) and chemotaxis (modified Boyden chamber). As Stamp2 deficiency promotes higher expression of inflammatory cytokines (IL6, IL1b, MCP1, TNFa, CXCL12, qPCR) and increased numbers of CD68-positive cells in the lung, actions of Stamp2 in macrophages are potentially driving vascular remodeling in PH. To test this hypothesis, PASMC proliferation and chemotaxis were assessed in response to treatment with supernatants from primary thioglycolate-elicited peritoneal Stamp2−/− or WT-macrophages. These experiments revealed that supernatants from Stamp2−/− macrophages induced PASMC proliferation and chemotaxis significantly stronger, thus providing a link between inflammatory actions in Stamp2 deficiency and vascular remodeling. To gain further insights, a cytokine array was performed with supernatants from Stamp2−/− and WT-macrophages, revealing CXCL12 as the most relevant candidate. Experiments with neutralizing antibodies confirmed the role of CXCL12 in driving Stamp2's actions on vascular remodelling processes in PASMC. Importantly, Stamp2 expression (qPCR, western blot analyses) was significantly lower in the lung of humans with idiopathic PAH (IPAH), as well as in experimental PH in rats (monocrotalin, sugen/hypoxia) and in mice (hypoxia). Conclusions Stamp2 deficiency aggravates hypoxia-induced pulmonary vascular remodeling and pulmonary hypertension in mice. On the cellular level, actions of Stamp2 in macrophages drive vascular remodelling processes in smooth muscle cells via secreted factors such as CXCL12. The finding of decreased expression of Stamp2 in human and various experimental forms of PH points towards a general protective role of Stamp2.

scholarly journals Overexpressed lncRNA AC068039.4 contributes to proliferation and cell cycle progression of pulmonary artery smooth muscle cells via sponging miR-26a-5p/TRPC6 in hypoxic pulmonary arterial hypertension

2020 ◽  
Author(s):  
Yuhan Qin ◽  
Boqian Zhu ◽  
Linqing Li ◽  
Gaoliang Yan ◽  
Dong Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Artery Smooth Muscle ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background: Hypoxic pulmonary hypertension (HPH) is a devastating and incurable disease characterized by pulmonary vascular remodeling, resulting to right heart failure and even death. Accumulated evidence has confirmed long coding RNAs (lncRNAs) are involved in hypoxia induced pulmonary vascular remodeling in HPH. The exact mechanism of lncRNA in hypoxic pulmonary hypertension remains unclear. Methods：Microarray analysis was applied to investigate the profiles of lncRNA expression in pulmonary artery smooth muscle cells (PASMCs) cultured under hypoxia and normoxia condition. qRT-PCR was performed for the expression of lncRNAs, miRNA and mRNAs, western blot analysis was employed for detection the expression of proteins. CCK-8 and transwell chamber assay were applied for assessment of PASMC proliferation and migration, respectively. Besides, flow cytometry was performed for assessments of cell cycle progression. The binding between AC068039.4 and miR-26a-5p, miR-26a-5p and TRPC6 3’UTR were detected by dual luciferase reporter assay.Results：A total of 1211 lncRNAs (698 up-regulated and 513 down-regulated) were differently expressed in hypoxia induced PASMCs. Consistent with microarray analysis, quantitative PCR verified that AC068039.4 was obviously up-regulated in hypoxia induced PASMCs. Knocking down AC068039.4 alleviated proliferation and migration of PASMCs and regulated cell cycle progression through inhibiting cells entering the G0/G1 cell cycle phase. Further experiment indicated AC068039.4 promoted hypoxic PASMCs proliferation via sponging miR-26-5p. In addition, transient receptor potential canonical 6 (TRPC6) was confirmed to be a target gene of miR-26a-5p. Conclusion: In conclusion, downregulation of lncRNA AC068039.4 inhibited pulmonary vascular remodeling through AC068039.4/miR-26a-5p/TRPC6 axis, providing new therapeutic insights for the treatment of HPH.

scholarly journals The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

2021 ◽  
Vol 22 (9) ◽  
pp. 4980
Author(s):  
Inés Roger ◽  
Javier Milara ◽  
Paula Montero ◽  
Julio Cortijo
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Clinical Manifestations ◽  
Different Types ◽  
Artery Remodeling ◽  
Stat Pathway ◽  
Pulmonary Artery Remodeling

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

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