Biology subjects

Szulcek, R.

Publications and source records attributed to Szulcek, R..

4 recordsLinked to original sources

bioRxiv2026

Differential multi-omics analysis of pulmonary arterial hypertension microvascular endothelial cells for differential drug response

Pulmonary arterial hypertension (PAH) represents a heterogeneous group of disorders that involves complex molecular dysregulations, which are not fully captured by single-omics analyses. We apply our network-based multi-omics analysis framework, DrDimont, to transcriptomic, proteomic, phosphoproteomic, and kinase screening data from lung microvascular endothelial cells of PAH patients and controls. Thereby, we extend the functionality of DrDimont to incorporate kinase-kinase interactions during the construction of condition-specific multi-omics networks. Kinase interactions are inferred from phosphorylations of screened substrates that are weighted by kinase-substrate predictions. Differential interaction scores from the network-based analysis between PAH and control uncover alterations centered on kinases, in particular top hits relating to MAPK signaling, such as MAPK13, MAP2K, or upstream IRAK1, and other MAPK/MAP2K family members. Further highly differential nodes were ACADSB, GPX7, DSE (for proteins), and AIM1, LY96, CHSY3 (for mRNAs). When prioritizing drug candidates by mapping drug targets onto the differential network, we find high scores for the drug tacrolimus (FK506) and several anti-neoplastic MAPK inhibitors (e.g., selumetinib, trametinib), as well as agents acting on general proliferation via (mitochondrial) DNA transcription (e.g., epirubicin, topotecan). Integrating kinase activity screens into our explainable multi-omics network-based analyses reveals kinase-centered alterations and therapeutic hypotheses in PAH that complement single-layer classical differential expression analyses.

bioinformatics↗

bioRxiv2025

BMP9 regulates the endothelial secretome to drive pulmonary hypertension

BMP9, a pleiotropic growth factor cytokine that regulates endothelial function, is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Loss-of-function mutations in GDF2 are found in heritable PAH, suggesting its function as an endothelial quiescence factor, while agonizing or antagonizing BMP9 signaling are both reported to ameliorate experimental pulmonary hypertension (PH). This study sought to resolve the contribution of BMP9 to pulmonary vascular disease and its status as a potential therapeutic target. The function of BMP9 in experimental PH was interrogated using recombinant BMP9, BMP9/BMP10 ligand trap ALK1-Fc, two anti-BMP9 neutralizing antibodies, and the activin/GDF/BMP ligand trap ACTRIIA-Fc (a.k.a., sotatercept). Disulfide-linked, prodomain complexed BMP9 was not protective in SUGEN-hypoxia or monocrotaline-induced PH models, in contrast to previous studies using incompletely disulfide-linked BMP9. In comparison, selective and non-selective BMP9 antagonism exerted prophylactic and therapeutic effects across PH models. Anti-BMP9 and ACTRIIA-Fc had comparable impact on hemodynamics, RV hypertrophy, and vascular remodeling, while single nucleus RNA-Seq revealed similar inhibition of SMAD1/5 and SMAD2/3 transcriptional activity, and highly overlapping DEGs, particularly in the endothelial compartment (r=0.83, p=2.54e-43, Spearman), suggesting overlap of mechanism in targeting BMP9. A multi-omic approach using lung tissues from human PAH, experimental models of pulmonary hypertension, and transcriptomic analysis of pulmonary microvascular endothelial cells from PAH patients revealed that BMP9 is critical for regulating several endothelial gene products that are overexpressed in human and experimental disease and implicated in disease pathogenesis including CXCL12, PDGF-BB, EDN1, COL18A1, and IGFBP4, and are inhibited by administering anti-BMP9 neutralizing antibodies or ligand traps. Co-culture studies revealed paracrine effects of BMP9-stimulated PMVEC on pulmonary arterial smooth muscle cell (PASMC) phenotypic plasticity, which could be attributed in large part to endothelial-derived CXCL12. In summary, endothelial BMP9 signaling is a key coordinator of vasoactive endothelial gene products that modulate PASMC phenotype and appears to be a shared target of anti-BMP9 and ACTRIIA-Fc. Selective targeting of endothelial BMP9 angiogenic signaling represents a potential therapeutic strategy for human PAH. One sentence summaryInhbiition of BMP9 signaling via different selective and non-selective strategies, including ACTRIIA-Fc/sotatercept, attenuates endothelial expression of vasoactive secreted factors that drive pulmonary vascular remodeling.

physiology↗

bioRxiv2024

Pneumonia induced rise in glucagon promotes endothelial damage and vascular thrombogenicity

BackgroundRecent studies have demonstrated a link between respiratory infections and increased short-term risk of cardiovascular disease (CVD). However, the molecular mechanisms underlying the increased cardiovascular risk after respiratory infections are only poorly understood. Here, we aimed to decipher pathophysiological circuits of pneumonia associated CVD in experimental models of bacterial pneumonia and vascular injury. MethodsC57BL/6J mice were exposed to intranasal inoculation with either Streptococcus pneumoniae (S. pneumoniae) serotype 4 (pneumonia group) or phosphate buffered saline (PBS) (control group). 24 hours post infectionem (p.i.) mice were treated with antibiotics until the end of the study. On day 7 p.i. carotid artery injury (CI) was induced by electric stimulation and vascular repair was analyzed 3 days after injury. Plasma proteomic analyses were performed by Olink Bioscience. Primary human aortic endothelial cells (HAECs) were used to study alterations of the endothelial functional properties, bioenergetic state and thrombogenic potential in vitro. Intravital fluorescence microscopy equipped with video recording was applied to measure thrombus formation in real-time. ResultsBacterial pneumonia impaired repair capacity of the endothelium after vascular injury. Proteomic analyses revealed significantly higher plasma levels of glucagon in mice after recovery from pneumonia relative to controls, which was further confirmed by ELISA detecting glucagon. Mechanistically, we found that glucagon impaired mitochondrial bioenergetics and migratory potential in HAECs and induced an inflammatory response. Moreover, glucagon fostered vascular thrombogenicity as demonstrated by increased thrombocyte adhesion to HAECs and accelerated carotid artery thrombus formation in vivo. Acute application of the glucagon-like peptide-1 receptor (GLP1-R) agonist liraglutide to lower blood glucagon levels, restored vascular repair potential and attenuated vascular thrombogenicity in mice with pneumonia. ConclusionsOur findings reveal a novel mechanism that associates elevated circulatory glucagon levels to dysfunctional endothelium and increased vascular thrombogenicity, suggesting glucagon signaling as a potential therapeutic target to prevent pneumonia-induced cardiovascular events. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/592488v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1dab59eorg.highwire.dtl.DTLVardef@1c9a033org.highwire.dtl.DTLVardef@34a566org.highwire.dtl.DTLVardef@56e33d_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2019

Krüppel-like factor 2- induced microRNAs: implications for treatment of pulmonary hypertension

Flow-activated transcription factor Kruppel-like factor 2 (KLF2) signaling is compromised in pulmonary arterial hypertension (PAH). We aimed to identify KLF2-induced endothelium-protective exosomal microRNAs of potential therapeutic significance.\n\nEight exosomal microRNAs elevated by KLF2 but reduced in PAH were transfected into human pulmonary artery endothelial cells. Of these, only miR-181a-5p and miR-324-5p had anti-apoptotic, anti-inflammatory and anti-proliferative effect on endothelial cells and reduced proliferation of vascular smooth muscle cells in vitro. RNA sequencing of miRNA-transfected HPAECs revealed reduced expression of multiple genes implicated in vascular remodelling, including ETS-1, NOTCH4, ACTA2, TNF-, IL-1, MMP10, MAPK and NFATC2. KLF2, miR-181a-5p and miR-324-5p were reduced, while their target genes were elevated in blood-derived endothelial colony forming cells and lung tissues from idiopathic and heritable PAH patients with disabling KLF2 mutation and Sugen/hypoxia mice. Supplementation of miR-181a-5p and miR-324-5p or silencing of their target genes attenuated proliferative and angiogenic responses in endothelial cells from idiopathic PAH and prevented development of pulmonary hypertension in Sugen/hypoxia mice.\n\nThis study highlights potential therapeutic role of KLF2-induced exosomal microRNAs in PAH.

cell biology↗