pulmonary artery smooth muscle
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2021 ◽  
Vol 12 ◽  
Author(s):  
Fenling Fan ◽  
Yifan Zou ◽  
Yousen Wang ◽  
Peng Zhang ◽  
Xiaoyu Wang ◽  
...  

Background: Similarities in the biology of pulmonary hypertension and cancer suggest that anticancer therapies, such as sanguinarine, may also be effective in treating pulmonary hypertension. This, along with underlying biochemical pathways, is investigated in this study.Methods: Rats were subjected to 4-week hypoxia (or control) with or without sanguinarine treatment. In addition, pulmonary artery smooth muscle cells (PASMCs) were examined after 24–48 h hypoxia (with normoxic controls) and with or without sanguinirine. Pulmonary artery pressures and plasma survivin levels were measured in vivo. Ex vivo tissues were examined histologically with appropriate staining. mRNA and protein levels of survivin, HIF-1α, TGFb1, BMPR2, Smad3, P53, and Kv 1.2, 1.5, 2.1 were determined by real-time PCR and Western blot in PASMCs and distal PAs tissue. PASMC proliferation and changes of TGFb1 and pSmad3 induced by sanguinarine were studied using MTT and Western blot. Electrophysiology for Kv functions was measured by patch-clamp experiments.Results: Four-week hypoxia resulted in an increase in serum survivin and HIF-1α, pulmonary artery pressures, and pulmonary vascular remodeling with hypertrophy. These changes were all decreased by treatment with sanguinarine. Hypoxia induced a rise of proliferation in PASMCs which was prevented by sanguinarine treatment. Hypoxic PASMCs had elevated TGFb1, pSmad3, BMPR2, and HIF1α. These increases were all ameliorated by sanguinarine treatment. Hypoxia treatment resulted in reduced expression and function of Kv 1.2, 1.5, 2.1 channels, and these changes were also modulated by sanguinarine.Conclusion: Sanguinarine is effective in modulating hypoxic pulmonary vascular hypertrophy via the survivin pathway and Kv channels.


2021 ◽  
Vol 12 ◽  
Author(s):  
Yong-Jie Chen ◽  
Yi Li ◽  
Xian Guo ◽  
Bo Huo ◽  
Yue Chen ◽  
...  

Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is a critical pathological feature in the pathogenesis of pulmonary arterial hypertension (PAH), but the regulatory mechanisms remain largely unknown. Herein, we demonstrated that interferon regulatory factor 9 (IRF9) accelerated PASMCs proliferation by regulating Prohibitin 1 (PHB1) expression and the AKT-GSK3β signaling pathway. Compared with control groups, the rats treated with chronic hypoxia (CH), monocrotaline (MCT) or sugen5416 combined with chronic hypoxia (SuHx), and mice challenged with CH had significantly thickened pulmonary arterioles and hyperproliferative PASMCs. More importantly, the protein level of IRF9 was found to be elevated in the thickened medial wall of the pulmonary arterioles in all of these PAH models. Notably, overexpression of IRF9 significantly promoted the proliferation of rat and human PASMCs, as evidenced by increased cell counts, EdU-positive cells and upregulated biomarkers of cell proliferation. In contrast, knockdown of IRF9 suppressed the proliferation of rat and human PASMCs. Mechanistically, IRF9 directly restrained PHB1 expression and interacted with AKT to inhibit the phosphorylation of AKT at thr308 site, which finally led to mitochondrial dysfunction and PASMC proliferation. Unsurprisingly, MK2206, a specific inhibitor of AKT, partially reversed the PASMC proliferation inhibited by IRF9 knockdown. Thus, our results suggested that elevation of IRF9 facilitates PASMC proliferation by regulating PHB1 expression and AKT signaling pathway to affect mitochondrial function during the development of PAH, which indicated that targeting IRF9 may serve as a novel strategy to delay the pathological progression of PAH.


2021 ◽  
Author(s):  
Junting Zhang ◽  
Yiying Li ◽  
Yujie Chen ◽  
Xiufeng Yu ◽  
Hanliang Sun ◽  
...  

Abstract Pulmonary hypertension (PH) is a serious and fatal disease characterized by pulmonary vasoconstriction and pulmonary vascular remodeling. The excessive autophagy of pulmonary artery smooth muscle cells (PASMCs) is one of the important factors of pulmonary vascular remodeling. A number of studies have shown that circular RNA (circRNA) can participate in the onset of PH. Our previous studies have shown that circRNA calmodulin 4 (circ-calm4) is involved in the progression of hypoxic PH. However, the role of circ-calm4 on regulation of hypoxic PH autophagy has not been reported. In this study, we demonstrated for the first time that hypoxia-mediated upregulated circ-calm4 expression has a key regulatory effect on autophagy in hypoxia-induced PASMCs and hypoxic PH mouse models. Knockdown of circ-calm4 both in vivo and in vitro can inhibit the autophagy in PASMCs induced by hypoxia. We also performed bioinformatics predictions and conducted experiments to verify that circ-calm4 bound to the purine-rich binding protein (Purb) to promote its expression in the nucleus, thereby initiating the transcription of autophagy-related protein Beclin1. Interestingly, we found that Beclin1 transcription initiated by Purb was accompanied by a modification of Beclin1 super-enhancer to improve transcription activity and efficiency. Overall, our results confirm that the circ-calm4/Purb/Beclin1 signal axis is involved in the occurrence of hypoxia-induced PASMCs autophagy, and the novel regulatory mechanisms and signals transduction pathways in PASMC autophagy induced by hypoxia.


2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Genfa Xiao ◽  
Guili Lian ◽  
Tingjun Wang ◽  
Weixiao Chen ◽  
Wei Zhuang ◽  
...  

Abstract Background Transcription factor CREB is involved in the development of pulmonary hypertension (PH). However, little is known about the role and regulatory signaling of CREB in PH. Methods A series of techniques, including bioinformatics methods, western blot, cell proliferation and luciferase reporter assay were used to perform a comprehensive analysis of the role and regulation of CREB in proliferation of pulmonary artery smooth muscle cells (PASMCs) in PH. Results Using bioinformatic analysis of the differentially expressed genes (DEGs) identified in the development of monocrotaline (MCT)- and hypoxia-induced PH, we found the overrepresentation of CRE-containing DEGs. Western blot analysis revealed a sustained increase in total- and phosphorylated-CREB in PASMCs isolated from rats treated with MCT. Similarly, an enhanced and prolonged serum-induced CREB phosphorylation was observed in hypoxia-pretreated PASMCs. The sustained CREB phosphorylation in PASMCs may be associated with multiple protein kinases phosphorylated CREB. Additionally, hierarchical clustering analysis showed reduced expression of the majority of CREB phosphatases in PH, including regulatory subunits of PP2A, Ppp2r2c and Ppp2r3a. Cell proliferation analysis showed increased PASMCs proliferation in MCT-induced PH, an effect relied on CREB-mediated transcriptional activity. Further analysis revealed the raised intracellular labile zinc possibly from ZIP12 was associated with reduced phosphatases, increased CREB-mediated transcriptional activity and PASMCs proliferation. Conclusions CREB pathway was overactivated in the development of PH and contributed to PASMCs proliferation, which was associated with multiple protein kinases and/or reduced CREB phosphatases and raised intracellular zinc. Thus, this study may provide a novel insight into the CREB pathway in the pathogenesis of PH.


2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Weifang Zhang ◽  
Zeying Tao ◽  
Fei Xu ◽  
Qian Diao ◽  
Juan Li ◽  
...  

Pulmonary hypertension (PH) is occult, with no distinctive clinical manifestations and a poor prognosis. Pulmonary vascular remodelling is an important pathological feature in which pulmonary artery smooth muscle cells (PASMCs) phenotypic switching plays a crucial role. MicroRNAs (miRNAs) are a class of evolutionarily highly conserved single-stranded small noncoding RNAs. An increasing number of studies have shown that miRNAs play an important role in the occurrence and development of PH by regulating PASMCs phenotypic switching, which is expected to be a potential target for the prevention and treatment of PH. miRNAs such as miR-221, miR-15b, miR-96, miR-24, miR-23a, miR-9, miR-214, and miR-20a can promote PASMCs phenotypic switching, while such as miR-21, miR-132, miR-449, miR-206, miR-124, miR-30c, miR-140, and the miR-17~92 cluster can inhibit it. The article reviews the research progress on growth factor-related miRNAs and hypoxia-related miRNAs that mediate PASMCs phenotypic switching in PH.


2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
R Ramadhiani ◽  
K Ikeda ◽  
K Miyagawa ◽  
G R T Ryanto ◽  
N Tamada ◽  
...  

Abstract Background Despite recently developed clinical therapies, vascular remodelling in pulmonary arterial hypertension (PAH) progressively worsen. Hemodynamic unloading has been proposed to normalize the remodelled pulmonary vascular structures in the lungs. Recently, it has been reported that cellular senescence was associated with the irreversibility of pulmonary vascular structures after hemodynamic unloading. Purpose This study aims to elucidate the role of senescent endothelial cells (ECs) in the pathogenesis of PAH. Methods We generated EC-specific progeroid mice in which ECs undergo premature senescence by overexpressing the dominant-negative form of telomere repeat-binding factor 2 under the control of the VE-cadherin promoter. Following three weeks of hypoxia exposure, the PH phenotypes were assessed by RVSP, lung histology, and RT-qPCR. The interaction of human pulmonary artery ECs (hPAECs) and human pulmonary artery smooth muscle cells (hPASMCs) was indirectly and directly explored through the co-culture system. Gamma-secretase inhibitor (DAPT) was administrated to inhibit Notch signalling both in the in-vitro and in-vivo study. Results EC-specific progeroid mice showed exacerbated pulmonary hypertension after chronic hypoxia exposure, accompanied by the enhanced medial SMCs proliferation in the distal pulmonary arteries. Contact-mediated interaction with senescent hPAECs increased proliferation and migration capacities in hPASMCs, while no such effects were detected in the absence of ECs-SMCs contact. Consistently, senescent ECs highly expressed Notch ligands, thus activated Notch signalling in hPASMCs, leading to increased Notch target genes in hPASMCs. Pharmacological inhibition of Notch signalling attenuated the enhanced SMCs proliferation and migration induced by senescent hPAECs, as well as the worsened PH phenotypes in EC-specific progeroid mice. Conclusions Our data established a crucial role of senescent ECs in the PAH pathogenesis through the dysregulated SMC functions via juxtacrine signaling. Senescent ECs are attracting targets for further pathological-targeted therapy to cure PAH completely. FUNDunding Acknowledgement Type of funding sources: None.


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