Osteopontin in Pulmonary Hypertension

Mamazhakypov, Argen; Maripov, Abdirashit; Sarybaev, Akpay; Schermuly, Ralph T.; Sydykov, Akylbek

doi:10.3390/biomedicines11051385

Cited by 4 publications

(4 citation statements)

References 120 publications

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“…The accumulating evidence underscores OPN’s role as an effective biomarker and mediator for cardiovascular disease, PH progression, severity, and prognosis ( 37 ). Given that OPN is a secreted circulating protein, it offers the advantage of non-invasive assessment through peripheral blood sampling ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

Integrative bioinformatics approach for identifying key genes and potential therapeutic targets in the concurrent manifestation of hypertrophic cardiomyopathy and pulmonary hypertension

Zheng,

Zhang,

Yang

et al. 2024

J Thorac Dis

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Background Hypertrophic cardiomyopathy (HCM), identified as a primary cause of sudden cardiac death (SCD), intertwines with pulmonary hypertension (PH) to amplify cardiovascular morbidity. This complex synergy poses significant therapeutic challenges due to the absence of drugs specifically targeting their concurrent manifestation. This study seeks to unravel the molecular intricacies linking HCM and PH, aiming to lay the groundwork for targeted therapeutic interventions. Methods Through the analysis of gene expression profiles from datasets GSE36961 (HCM) and GSE113439 (PH) within the public data repository of Gene Expression Omnibus (GEO), this research systematically identified differentially expressed genes (DEGs), conducted extensive functional annotations, and constructed detailed protein-protein interaction (PPI) networks to uncover crucial hub genes. Further, co-expression analyses, alongside drug prediction and molecular docking simulations, were employed to pinpoint potential therapeutic agents that could ameliorate the combined pathology of HCM and PH. Results Our comprehensive analysis unearthed 79 DEGs shared between HCM and PH, highlighting fourteen as pivotal hub genes. Validation across three additional datasets (GSE35229, GSE32453, and GSE53408) from GEO accentuated secreted phosphoprotein 1 ( SPP1 ) as a key gene of interest. Remarkably, the study identified tacrolimus, ponatinib, bosutinib, dasatinib, doxorubicin, and zanubrutinib as promising drugs for addressing the dual challenge of HCM and PH. Conclusions The findings of this investigation shed light on the genetic underpinnings of HCM and PH’s simultaneous occurrence, emphasizing the central role of SPP1 in their pathogenesis. The identification of six candidate drugs offers a hopeful vista for future therapeutic strategies targeting this complex cardiovascular interplay, marking a significant stride towards mitigating the compounded morbidity of HCM and PH. Future mechanistic and clinical studies are warranted for the investigation of this potential target and therapeutics.

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Section: Discussionmentioning

confidence: 99%

Integrative bioinformatics approach for identifying key genes and potential therapeutic targets in the concurrent manifestation of hypertrophic cardiomyopathy and pulmonary hypertension

Zheng,

Zhang,

Yang

et al. 2024

J Thorac Dis

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“…Indeed, in humans, the presence of pulmonary hypertension is associated with higher circulating SPP1 levels compared to healthy patients. 28 However, development of pulmonary hypertension might also be secondary to the higher SPP1 level found in dogs with IPF as SPP1 might induce vascular remodeling. 28 SPP1 was higher in the serum of WHWTs affected with IPF compared with control WHWTs and other control terriers and could be used as a diagnostic biomarker with a moderate diagnostic accuracy.…”

Section: Discussionmentioning

confidence: 99%

“…Pulmonary hypertension, which was identified in 54% of WHWTs with IPF, might also be 1 of the factors that explained the higher SPP1 concentration in WHWTs with IPF compared with healthy WHWTs. Indeed, in humans, the presence of pulmonary hypertension is associated with higher circulating SPP1 levels compared to healthy patients 28 . However, development of pulmonary hypertension might also be secondary to the higher SPP1 level found in dogs with IPF as SPP1 might induce vascular remodeling 28 …”

Section: Discussionmentioning

confidence: 99%

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Osteopontin and fibronectin in lung tissue, serum, and bronchoalveolar lavage fluid of dogs with idiopathic pulmonary fibrosis and control dogs

Fastrès,

Roels,

Tutunaru

et al. 2023

Veterinary Internal Medicne

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BackgroundIdiopathic pulmonary fibrosis (IPF) affects West Highland white terriers (WHWTs). Osteopontin (SPP1) and fibronectin (FN1) are associated with human IPF and are overexpressed by bronchoalveolar lavage fluid (BALF) macrophages in dogs with IPF.ObjectiveTo investigate the value of these proteins as biomarkers of IPF.AnimalsWest Highland white terriers (WHWTs) with IPF, control WHWTs, and terriers.MethodsCross‐sectional observational study. Immunohistochemistry was used to localize SPP1 and FN1 in lung tissue. Serum and BALF SPP1 and FN1 concentrations were measured using canine ELISA kits and compared between groups.ResultsOsteopontin stained ciliated epithelial cells, smooth muscular cells, and macrophages of all included dogs, and type‐II pneumocytes and extracellular matrix of all 12 diseased WHWTs, 4/6 control WHWTs, and none of the 3 terriers. Osteopontin serum concentration was higher in diseased WHWTs (n = 22; 2.15 ng/mL [0.74‐5.30]) compared with control WHWTs (n = 13; 0.63 ng/mL [0.41‐1.63]; P = .005) and terriers (n = 15; 0.31 ng/mL [0.19‐0.51]; P < .0001), and in control WHWTs compared with terriers (P = .005). Osteopontin BALF concentrations were higher in diseased (0.27 ng/mL [0.14‐0.43]) and control WHWTs (0.25 ng/mL [0.14‐0.40]), compared with terriers (0.02 ng/mL [0.01‐0.08]; P < .0001 and P = .003, respectively). Fibronectin (FN1) serum concentrations were lower in diseased dogs (1.03 ng/mL [0.35‐1.48]) and control WHWTs (0.61 ng/mL [0.24‐0.65]) compared with terriers (2.72 ng/mL [0.15‐5.21]; P < .0001 and P = .0001, respectively). There was no difference in FN1 immunostaining and FN1 BALF concentrations between groups.ConclusionsResults suggest that SPP1 is involved in pathogenesis of IPF and could predispose that breed to the disease. Osteopontin serum concentration could serve as a diagnostic biomarker of IPF.

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Single tyrosine mutation in VE-cadherin modulates gene lung expressions: evidence for FOXF1 mediated S1PR1 upregulation to stabilize vessels in mice

Garnier,

Jeanneret,

Durand

et al. 2023

Preprint

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Rationale: Phosphorylation-dephosphorylation are processes involved in the adhesion of endothelial cells (ECs) to maintain vascular integrity in adults. VE-cadherin is a target for Src -mediated Y685 phosphorylation, identified in highly vascularized human glioblastoma where it is involved in the abnormal feature of tumor blood vessels . Objective: We aimed at understanding the molecular mechanisms through which Y685F-VE-cadherin triggers S1PR1 gene expression and stabilizes lung vessels in adult mice. Methods and Results: We compared lung ECs from a knock-in (KI) mouse carrying a point mutation in VE-cadherin (Tyr 685 to Phe) to Wild type . Analysis of EC parameters showed a difference in the migratory rate was between ECs from KI (22.45% +/- 5.207) and WT (13.24% +/- 5.17) (p-value=0.034). The direct adhesion of ECs from KI mice to fibronectin was significantly higher (37.625 +/- 9.23) than that of the WT (26.8 +/- 3.258, p-value=0.012). In the fibrin bead assay, ECs from KI showed a weaker angiogenic response. The transcriptome of mutated ECs showed that 884 genes were dysregulated of which 766 genes were downregulated and 118 genes were upregulated. The Gene Ontology Enrichment showed that most of the genes were related to cell-cell adhesion and angiogenesis. Focusing on angiogenic genes, we found that Sphingosine-1-phosphate-receptor was a gene upregulated in mutated ECs which was confirmed by RT-PCR and westernblotting. Mechanistically, chromatin immunoprecipitation assay (CHIPS) demonstrated that FOXF1 directly bound to the S1pr1 promoter 7 fold greater than WT. As a consequence , VE-cadherin at the membrane was higher in the mutant vs WT (100 +/- 6.52 for WT vs 189.7 +/- 21.06 for KI (p-value 0.0001). Finally, lung morphometric analysis showed less vessels and vascular remodeling with no fibrosis in mutated mice. Conclusions: These data extend our knowledge on pY-VE-cadherin mediated pathological angiogenesis and provide new therapeutic opportunities to vascular normalization through pharmacological inhibition of the Y685-VE-cadherin phosphorylation.

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Osteopontin in Pulmonary Hypertension

Cited by 4 publications

References 120 publications

Integrative bioinformatics approach for identifying key genes and potential therapeutic targets in the concurrent manifestation of hypertrophic cardiomyopathy and pulmonary hypertension

Integrative bioinformatics approach for identifying key genes and potential therapeutic targets in the concurrent manifestation of hypertrophic cardiomyopathy and pulmonary hypertension

Osteopontin and fibronectin in lung tissue, serum, and bronchoalveolar lavage fluid of dogs with idiopathic pulmonary fibrosis and control dogs

Single tyrosine mutation in VE-cadherin modulates gene lung expressions: evidence for FOXF1 mediated S1PR1 upregulation to stabilize vessels in mice

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