Calpain‐1 mediates vascular remodelling and fibrosis via HIF‐1α in hypoxia‐induced pulmonary hypertension

Deng, Hongkui; Tian, Xinhui; Sun, Hening; Liu, Huan; Lü, Meili; Wang, Hongxin

doi:10.1111/jcmm.17295

Cited by 26 publications

(6 citation statements)

References 37 publications

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“…51 UBXN7 regulates HIF-1α, glycolysis, and oxidative phosphorylation levels under hypoxia. 52 Moreover, as HIF-1 α is highly expressed in the lungs of HPH mice, 53 our subsequent research will concentrate on investigating the regulatory relationship between UBXN7 and HIF-1α in HPH.…”

Section: Discussionmentioning

confidence: 99%

Weighted gene co-expression network analysis reveals the hub genes associated with pulmonary hypertension

Wang

D²,

Liu

et al. 2023

Exp Biol Med (Maywood)

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Pulmonary hypertension (PH) is a cardiopulmonary vascular disease that acutely endangers human health and can be fatal. It progresses rapidly and has a high mortality rate. Its pathophysiology is complicated and still not completely elucidated; therefore, achieving treatment breakthroughs are difficult. In this study, data from 58 normal controls and 135 patients with PH were extracted from the GSE24988, GSE113439, and GSE117261 datasets in the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (DEGs). In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Weighted gene co-expression network analysis (WGCNA) was used to identify the key modules and hub genes associated with PH. Eight PH-associated hub genes were identified. Furthermore, correlation analysis between immune cell infiltration and hub genes was performed, and the receiver operating characteristic (ROC) curves showed that TARDBP had the best diagnostic efficacy. Moreover, a rat hypoxic pulmonary hypertension (HPH) model was generated, and the expression of hub genes in the lungs and pulmonary arteries of HPH rats was verified using western blotting assays. Our results showed that mTOR, PSMD2, RBM8A, SMARCA4, TARDBP, and UBXN7 were highly expressed in the lungs. In addition, EFTUD2, mTOR, RBM8A, SMARCA4, TARDBP, and UBXN7 were significantly upregulated, whereas DDB1 was significantly downregulated in the pulmonary arteries of HPH rats compared with those of controls. In conclusion, we identified PH hub genes with diagnostic and predictive value by performing WGCNA on data from the GEO database. Furthermore, we provided novel insights of PH that might be utilized to evaluate potential biomarker genes and therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Weighted gene co-expression network analysis reveals the hub genes associated with pulmonary hypertension

Wang

D²,

Liu

et al. 2023

Exp Biol Med (Maywood)

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“…Inhibition of calpain has been reported to inhibit the proliferation of vascular smooth muscle cells in diabetes [ 34 ]. In addition, studies using mouse models of hypoxia-induced pulmonary hypertension and pulmonary arterial smooth muscle cells suggest that calpain-1 may be important for hypoxia-inducible factor-1α-mediated vascular remodeling and fibrosis [ 35 ]. Therefore, although we were not able to evaluate vascular injury in the present study, further studies are needed to determine the utility of ALLN for vascular injury associated with SSc.…”

Section: Discussionmentioning

confidence: 99%

A cysteine proteinase inhibitor ALLN alleviates bleomycin-induced skin and lung fibrosis

Kasamatsu,

Chino,

Hasegawa

et al. 2023

Arthritis Res Ther

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Background Systemic sclerosis (SSc) is a connective tissue disease that is characterized by fibrosis in the skin and internal organs, such as the lungs. Activated differentiation of progenitor cells, which are mainly resident fibroblasts, into myofibroblasts is considered a key mechanism underlying the overproduction of extracellular matrix and the resultant tissue fibrosis in SSc. Calpains are members of the Ca2+-dependent cysteine protease family, whose enzymatic activities participate in signal transduction and tissue remodeling, potentially contributing to fibrosis in various organs. However, the roles of calpain in the pathogenesis of SSc remain unknown. This study aimed to examine the anti-fibrotic properties of N-acetyl-Leu-Leu-norleucinal (ALLN), one of the cysteine proteinase inhibitors that primarily inhibit calpain, in vitro and in vivo, to optimally translate into the therapeutic utility in human SSc. Methods Normal human dermal and lung fibroblasts pretreated with ALLN were stimulated with recombinant transforming growth factor beta 1 (TGF-β1), followed by assessment of TGF-β1/Smad signaling and fibrogenic molecules. Results ALLN treatment significantly inhibited TGF-β1-induced phosphorylation and nuclear transport of Smad2/3 in skin and lung fibroblasts. TGF-β1-dependent increases in α-smooth muscle actin (αSMA), collagen type I, fibronectin 1, and some mesenchymal transcription markers were attenuated by ALLN. Moreover, our findings suggest that ALLN inhibits TGF-β1-induced mesenchymal transition in human lung epithelial cells. Consistent with these in vitro findings, administering ALLN (3 mg/kg/day) three times a week intraperitoneally remarkably suppressed the development of skin and lung fibrosis in a SSc mouse model induced by daily subcutaneous bleomycin injection. The number of skin- and lung-infiltrating CD3+ T cells decreased in ALLN-treated mice compared with that in control-treated mice. Phosphorylation of Smad3 and/or an increase in αSMA-positive myofibroblasts was significantly inhibited by ALLN treatment on the skin and lungs. However, no adverse effects were observed. Conclusions Our results prove that calpains can be a novel therapeutic target for skin and lung fibrosis in SSc, considering its inhibitor ALLN.

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“…Vascular remodeling plays a critical factor in the pathogenesis of HPH, with the proliferation and hypertrophy of PASMCs significantly contributing to this process 32 . To elucidate the involvement of OPN, PI3K-AKT, and autophagy in vitro, PASMCs were cultured (Fig.…”

Section: Resuitsmentioning

confidence: 99%

OPN silencing reduces hypoxic pulmonary hypertension via PI3K-AKT-induced protective autophagy

Zhou,

Li,

Ding

et al. 2024

Sci Rep

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Hypoxic pulmonary hypertension (HPH) is a pulmonary vascular disease primarily characterized by progressive pulmonary vascular remodeling in a hypoxic environment, posing a significant clinical challenge. Leveraging data from the Gene Expression Omnibus (GEO) and human autophagy-specific databases, osteopontin (OPN) emerged as a differentially expressed gene, upregulated in cardiovascular diseases such as pulmonary arterial hypertension (PAH). Despite this association, the precise mechanism by which OPN regulates autophagy in HPH remains unclear, prompting the focus of this study. Through biosignature analysis, we observed significant alterations in the PI3K-AKT signaling pathway in PAH-associated autophagy. Subsequently, we utilized an animal model of OPNfl/fl-TAGLN-Cre mice and PASMCs with OPN shRNA to validate these findings. Our results revealed right ventricular hypertrophy and elevated mean pulmonary arterial pressure (mPAP) in hypoxic pulmonary hypertension model mice. Notably, these effects were attenuated in conditionally deleted OPN-knockout mice or OPN-silenced hypoxic PASMCs. Furthermore, hypoxic PASMCs with OPN shRNA exhibited increased autophagy compared to those in hypoxia alone. Consistent findings from in vivo and in vitro experiments indicated that OPN inhibition during hypoxia reduced PI3K expression while increasing LC3B and Beclin1 expression. Similarly, PASMCs exposed to hypoxia and PI3K inhibitors had higher expression levels of LC3B and Beclin1 and suppressed AKT expression. Based on these findings, our study suggests that OPNfl/fl-TAGLN-Cre effectively alleviates HPH, potentially through OPN-mediated inhibition of autophagy, thereby promoting PASMCs proliferation via the PI3K-AKT signaling pathway. Consequently, OPN emerges as a novel therapeutic target for HPH.

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Calpain‐1 mediates vascular remodelling and fibrosis via HIF‐1α in hypoxia‐induced pulmonary hypertension

Cited by 26 publications

References 37 publications

Weighted gene co-expression network analysis reveals the hub genes associated with pulmonary hypertension

Weighted gene co-expression network analysis reveals the hub genes associated with pulmonary hypertension

A cysteine proteinase inhibitor ALLN alleviates bleomycin-induced skin and lung fibrosis

OPN silencing reduces hypoxic pulmonary hypertension via PI3K-AKT-induced protective autophagy

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