Higher soluble thrombomodulin and angiogenic markers in continuous flow left ventricular assist device-supported patients associated with arteriovenous malformation and nonsurgical bleedingMuthiah, Dunn, Eckford
et alJHLT Open (2024) 6, 100133
Abstract: Bleeding complications are a bane of continuous flow left ventricular assist devices (cfLVAD); gastrointestinal bleeding (GIB) from arteriovenous malformation (AVM) predominating. We hypothesized that shear stress disrupts vascular endothelium altering angiogenesis and contributing to bleeding. We profiled markers of endothelial dysfunction (soluble thrombomodulin [sTM]) and angiogenesis (angiopoietin-1 [Ang-1], angiopoietin-2 [Ang-2]) in 21 patients implanted with a centrifugal cfLVAD. Bleeding episodes were documented in 11 patients, 8 had GIB, 4 of whom had AVMs. We observed a dynamic change in sTM and Ang-2/Ang-1 ratio following cfLVAD support (p = 0.030 and p = 0.025, respectively). Bleeding patients had higher sTM and Ang-2/Ang-1 ratios than patients with no bleeding (p = 0.04 and p = 0.06, respectively). At D180, patients with AVMs had significantly higher Ang-2/Ang-1 ratios vs patients without proven AVMs (p = 0.006). We conclude that bleeding in cfLVAD-supported patients is associated with alteration in endothelial/vascular homeostasis, possibly contributing to AVM formation.© 2024 International Society for Heart and Lung Transplantation.
Angiopoietin-2 and D-dimer add prognostic information to clinical risk in pulmonary arterial hypertensionClark, Lachant, Light
et alJHLT Open (2025) 7, 100178
Abstract: Thrombosis and endothelial injury are pathologic hallmarks of pulmonary arterial hypertension (PAH). We aimed to evaluate whether markers of endothelial dysfunction and coagulation in the blood would provide insight into disease activity, treatment response, and outcomes in PAH.We prospectively collected baseline and 3-month follow-up blood samples from treatment-naïve patients with PAH (n = 22) and those who had a clinical indication to intensify therapy (n = 19). In addition, we recruited 12 healthy people and clinically stable patients with PAH (n = 45) as controls who had 2 blood samples collected twice within 14 days. We generated platelet-free plasma and measured D-dimer, angiopoietin-2, thrombin time, soluble P-selectin, von Willebrand factor, and vascular endothelial growth factor. We assessed treatment response with Reveal Lite 2 scores (all patients had N-terminal-pro-brain natriuretic peptide, 6-minute walk, and functional class assessment at both visits) and followed clinical outcomes for 3 years.Angiopoietin-2 levels were elevated and fell in response to effective therapy (drop in Reveal Lite 2 score). At follow-up, persistently elevated angiopoietin-2 levels predicted clinical events and even identified low-risk participants who subsequently had events. D-dimer levels were also elevated in patients with PAH but did not change in response to therapy. Several other abnormalities in endothelial and platelet activation were identified (including elevated soluble P-selectin, elevated von Willebrand factor, and elevated vascular endothelial growth factor) but these did not change with treatment or predict outcome.Angiopoietin-2 and D-dimer are elevated in patients with PAH and may add prognostic information to routine clinical assessment.© 2025 International Society for Heart and Lung Transplantation.
Human lung microvascular endothelial cell protein modification by 2-chlorohexadecanoic acid: RhoA mediates 2-chlorohexadecanoic acid-elicited endothelial activationCarlson, Ford
Redox Biol (2025) 82, 103596
Abstract: Chlorolipids are produced during the neutrophil respiratory burst as a result of myeloperoxidase (MPO)-generated hypochlorous acid (HOCl) targeting the vinyl ether bond of plasmalogen phospholipids. The initial products of this reaction are 2-chlorofatty aldehydes (2-ClFALDs), which are subsequently oxidized to 2-chlorofatty acids (2-ClFAs). 2-Chlorohexadecanoic acid (2-ClHA) is the 16-carbon 2-ClFA species, and previous studies have shown that increased levels of plasma 2-ClHA associate with acute respiratory distress syndrome (ARDS)-caused mortality in human sepsis. 2-ClHA causes endothelial barrier dysfunction and increases neutrophil and platelet adherence to the endothelium. In this study, click chemistry analogs of 2-ClHA and hexadecanoic acid (HA) were used to identify proteins covalently modified by 2-ClHA and HA in human lung microvascular endothelial cells (HLMVECs). Eleven proteins were specifically modified by 2-ClHA, and an additional one hundred and ninety-four proteins were modified by both 2-ClHA and HA. STRING analysis of 2-ClHA-modified proteins revealed a network of proteins with RhoA as a hub. RhoA is one of the proteins specifically modified by 2-ClHA and not HA. The RhoA inhibitors, Rhosin and C3, inhibited both 2-ClHA-elicited HLMVEC barrier dysfunction and angiopoietin-2 (Ang-2) release from HLMVEC. Further studies showed 2-ClHA activates HLMVEC RhoA activity. The specificity of the 2-ClHA-RhoA pathway for endothelial activation was further confirmed since HA did not cause HLMVEC barrier dysfunction, Ang-2 release and RhoA activation. Collectively, these studies have identified multiple proteins modified exclusively by 2-ClHA in HLMVECs, including RhoA. These proteomics studies led to the key finding that RhoA is an important mediator of 2-ClHA-caused endothelial barrier dysfunction.Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.
Associations of ANGPT2 expression and its variants (rs1868554 and rs7825407) with multiple myeloma risk and outcomePopek-Marciniec, Styk, Chocholska
et alFront Oncol (2025) 15, 1468373
Abstract: The growth of blood vessels from the existing vasculature has a significant impact on the course of multiple myeloma (MM). The ANGPT2 (angiopoietin-2) protein is encoded by the ANGPT2 gene and plays an important role in angiogenesis. The expression of proangiogenic proteins is influenced not only by microenvironmental factors but also by genetic changes. We analyzed two variants/polymorphisms of the ANGPT2 gene, rs1868554 (T>A) and rs7825407 (G>C). Both are located in the intron sequence and can affect the final mRNA sequence by modifying splicing.Therefore, we assessed the impact of selected variants on ANGPT2 gene expression at the mRNA and protein levels. Additionally, we evaluated the associations of the analyzed genetic changes with the clinical and laboratory parameters of the disease and the response to bortezomib/thalidomide-based therapies. We hypothesize that variants and expression of the ANGPT2 gene may be associated with a greater risk of MM development and may also affect the response to treatment in MM patients.Genomic DNA extracted from 103 newly diagnosed MM patients and 120 healthy blood donors was used to analyze ANGPT2 variants (via automated DNA sequencing). RNA was subjected to real-time PCR to determine ANGPT2 expression at the mRNA level. The concentration of angiopoietin-2 (in MM sera) was determined by ELISA.The results of our study showed that individuals with the AA genotype of rs1868554 and the CC genotype of rs7825407 had a greater risk of developing MM (OR=6.12, p=0.02 and OR=6.01, p=0.02, respectively). The ANGPT2 gene variants did not affect ANGPT2 expression at the mRNA level. However, ANGPT2 expression was positively correlated with CRP (Spearman's rho 0.26, p<0.05) and negatively correlated with LDH (Spearman's rho -0.25, p<0.05) in MM patients.Our results showed that ANGPT2 expression at the mRNA level correlates with CRP, a negative prognostic factor in MM. The ANGPT2 protein is a proangiogenic factor, and its concentration is significantly greater in MM patients than in healthy individuals, which was also confirmed in our research. Therefore, this protein with VEGF and HB-EGF, should be considered in the future as a markers of angiogenesis in MM.Copyright © 2025 Popek-Marciniec, Styk, Chocholska, Szudy-Szczyrek, Sidor, Swiderska-Kolacz, Hus, Czerwik-Marcinkowska and Zmorzynski.
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