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Journal articleKelly JA, Salih M, Patel A, et al., 2026,
Editor's Choice - Aquaporin-4: A Predictor and Therapeutic Target for Permanent Paraplegia after Endovascular Thoraco-abdominal Aortic Aneurysm Repair.
, Eur J Vasc Endovasc Surg, Vol: 72, Pages: 491-499OBJECTIVE: Endovascular thoraco-abdominal aortic aneurysm (TAAA) repair can impair spinal cord perfusion, leading to paraplegia. The mechanisms driving this devastating complication are poorly understood. This study aimed to interrogate the cerebrospinal fluid (CSF) proteome in patients after TAAA repair to identify biomarkers that herald permanent paraplegia. It also aimed to investigate a potential therapeutic target identified by proteomics using an in vivo model of ischaemic spinal cord injury (iSCI). METHODS: CSF was collected for proteomic analysis from patients before and following TAAA repair. A differentially expressed protein identified in human paraplegic subjects was subsequently interrogated in a rodent model of iSCI. The protein composition of CSF was analysed using tandem mass tag proteomics. Neurological examinations were carried out by a blinded neurologist and T2 weighted magnetic resonance imaging (MRI) was used to measure spinal cord volume and oedema. A rodent model of iSCI was used to investigate a clinically relevant therapeutic target informed by proteomic findings. RESULTS: CSF analysis was taken from 37 patients, all of whom had aneurysm repair using a custom branched and or fenestrated device (median age 73.5 years, range 67 - 78 years; 27 men, ten women; Crawford classification: six type I, 11 type II, 15 type III, three type IV, and two type V). Five patients remained permanently paraplegic and seven recovered from transient paraplegia. The CSF of patients who remained paraplegic contained approximately fourfold more aquaporin-4 (AQP4) (41.8 ± 19.2 ng/mL, n = 5) than those who recovered from paraplegia (10.8 ± 1.3 ng/mL, n = 7; p = .005) or did not develop paraplegia (10.8 ± 1.2 ng/mL, n = 25; p = .004). Permanently paraplegic patients had CSF AQP4 levels > 15 ng/mL and this was associated with greater cord oedema on T2 weighted MRI (1.77 ± 0.19 vs. 1.03 ± 0.36; p = .032). In a rodent model of iSCI
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Journal articleTakov K, Penkov S, Pechlaner R, et al., 2026,
Lipoprotein(a) carries triglyceride species associated with incident cardiovascular disease.
, Atherosclerosis, Vol: 420BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is described as a low-density lipoprotein-like particle, but recent work suggests heterogeneity, including triglyceride (TG)-rich features. We investigated whether native Lp(a) carries an apolipoprotein E (APOE)-associated TG signature, whether it is remodeled postprandially, and whether Lp(a)-associated TG species are linked to cardiovascular risk. METHODS: Plasma Lp(a) was immunocaptured under native conditions and analyzed by proteomics in patients with high Lp(a) (n = 15) and lipidomics in healthy volunteers (n = 9). Lp(a) produced in HepG2 cells was characterized using immunoprecipitation, density gradient ultracentrifugation, microsomal triglyceride transfer protein inhibition, and fatty acid loading. Matched fasting and postprandial samples assessed Lp(a) lipidome remodeling (n = 6). The relationship between Lp(a)-associated TGs and cardiovascular risk was examined in the community-based Bruneck Study (n = 623). RESULTS: Direct plasma Lp(a) immunocapture showed APOE enrichment, confirmed by proteomics, immunoblotting, reverse APOE immunocapture, and size-exclusion chromatography followed by Lp(a) immunoprecipitation. In vitro, HepG2 cells secreted APOE-containing Lp(a) that was more buoyant than apolipoprotein B (APOB)-only particles and less affected by lomitapide or fatty acid loading. The Lp(a) lipidome was more stable postprandially than plasma lipids. Plasma Lp(a) depletion reduced 35 lipid species, predominantly TGs, including TG(52:3) and TG(52:4), previously linked to incident cardiovascular disease. TG reduction following Lp(a) depletion correlated with attenuation of cardiovascular risk after Lp(a) adjustment in the Bruneck Study, supporting a clinically relevant TG signature of native Lp(a). CONCLUSIONS: Native plasma Lp(a) carries a defined TG signature that is relatively stable postprandially and linked to incident cardiovascular disease.
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Journal articleYin S, Mayr U, Barallobre-Barreiro J, et al., 2026,
Aortic Stenosis Hyalectan Remodeling Revealed by Proteomics and Glycoproteomics.
, Arterioscler Thromb Vasc Biol, Vol: 46BACKGROUND: Calcific aortic valve (AV) disease (CAVD) is recognized as an active pathological process involving extracellular matrix remodeling. This study investigates extracellular matrix remodeling through proteomic analysis and a novel mouse model of aortic stenosis. METHODS: Proteomic and glycoproteomic analyses were conducted on AV leaflets from heart transplant donors (n=29) and patients with CAVD (n=17). Each CAVD sample was subdivided into noncalcified and calcified regions. To investigate the functional impact of extracellular matrix remodeling on aortic stenosis, we crossed apolipoprotein E-deficient mice (ApoE-/-) with mice lacking the catalytic domain of ADAMTS5 (Adamts5Δcat) to generate a mouse model combining hyalectan accumulation with hypercholesterolemia. RESULTS: Proteomic and glycoproteomic analyses revealed hyalectan accumulation in CAVD compared with control valves. Versican predominated in noncalcified regions, while aggrecan was enriched in calcified regions. The shift in hyalectan composition correlated with changes in AV pressure gradient, elevated osteoblast-like cell markers, and inflammatory proteins, most notably pentraxin 3. Both versican and aggrecan are characterized by their ability to bind hyaluronan and serve as substrates of ADAMTS5. In Adamts5Δcat/ApoE-/- mice, hyalectan accumulation was associated with narrowed aortic cusp separation and increased post-AV velocity. Proteomic analysis of AVs from Adamts5Δcat/ApoE-/- mice revealed elevated versican, aggrecan, and pentraxin 3, recapitulating key features of human CAVD. Single-cell RNA sequencing and in vitro experiments linked versican to activated valve interstitial cells, while aggrecan colocalized with calcification markers in osteoblast-like cells. Pentraxin 3 was bound to hyaluronan and accumulated in calcified AVs. ADAMTS5 deficiency was sufficient to cause intact versican accumulation and promote valve interstitial cell activation, accompanied by increased
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Journal articleMacko A, Pecon-Slattery J, Shovlin CL, 2026,
Translating evolutionary history and protein-focused machine learning supports increased prevalence of hereditary haemorrhagic telangiectasia, one of the most common inherited disorders
, QJM: An International Journal of Medicine, ISSN: 1460-2725<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Recent genetic data suggest hereditary haemorrhagic telangiectasia (HHT) is 2-12 times more common than the clinically-ascertained prevalence, potentially above the ‘rare disease’ designation threshold, and undermining clinical predictions for asymptomatic individuals diagnosed by genetic testing.</jats:p> </jats:sec> <jats:sec> <jats:title>Aim</jats:title> <jats:p>To test, we examined if missense variants in HHT disease-causing genes may have been misclassified as pathogenic (LP/P) or benign (B/LB).</jats:p> </jats:sec> <jats:sec> <jats:title>Design</jats:title> <jats:p>Evaluation of ClinVar-annotated missense variants in ENG, ACVRL1 and SMAD4.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Human-independent methods using CodeXome for pan-primate evolutionary history, and AlphaMissense which incorporates AlphaFold predictions for protein misfolding were used to validate/reclassify pathogenic and benign missense variants</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>ClinVar annotations were commonly conservative with 35-90% of rare missense substitutions in ENG, ACVRL1 and SMAD4 classified as variants of uncertain significance (VUS). CodeXome identified 92% of ClinVar-annotated B/LB variants were shared with other primate species, supporting their benign classification. AlphaMissense metrics strongly c
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Journal articleMoss BAS, Duregotti E, Yin X, et al., 2026,
Generation of Fibrin-Based Three-Dimensional Engineered Vascular Tissues from Human Aortic Smooth Muscle Cells for Proteomic Analysis.
, J Vis ExpVascular smooth muscle cells (SMCs) reside within the medial layer of blood vessels, where they interact with an extracellular matrix (ECM) composed of collagen, elastin, and proteoglycans to maintain vascular structure and function. Aberrant ECM remodeling contributes to multiple vascular diseases; however, conventional two-dimensional culture systems do not adequately recapitulate the three-dimensional (3D) cellular and matrix environment required to study SMC-ECM interactions and matrix remodeling. This protocol describes the generation of engineered vascular tissues (EVTs) from primary human aortic SMCs cultured within fibrin-based 3D hydrogels. Following casting between flexible polydimethylsiloxane posts, EVTs undergo cellular alignment, contraction, and deposit de novo ECM, providing a physiologically relevant platform for studying vascular matrix biology. The protocol details tissue fabrication, culture, harvesting, and downstream analysis of newly deposited ECM by immunofluorescence staining. In addition, a workflow is presented for qualitative and quantitative characterization of EVT-derived proteins using Western blotting and mass spectrometry-based proteomics. Sequential protein extraction enables assessment of soluble and ECM-enriched protein fractions, facilitating in-depth evaluation of ECM composition. This platform provides a reproducible approach for investigating ECM production and remodeling by human SMCs in a 3D environment.
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Journal articleSingh B, Mayr M, 2026,
Decoding Plaque Instability Through Plasma Proteomics Profiling?
, JACC Basic Transl Sci, Vol: 11 -
Journal articleKhawaja SA, Hanna L, Singh A, et al., 2026,
A randomised trial of carbon dioxide flushing to reduce vascular brain injury in patients undergoing TAVI.
, EuroIntervention, Vol: 22, Pages: 883-890BACKGROUND: Stroke remains a significant concern in patients undergoing transcatheter aortic valve implantation (TAVI). Despite advances in TAVI technology and techniques, stroke rates have remained unchanged, with trials of cerebral embolic protection devices failing to reduce rates. The concept of air emboli has not been previously investigated in TAVI procedures. We hypothesised that gaseous emboli could play a significant role in TAVI and that carbon dioxide (CO2) flushing of the TAVI valves could reduce the incidence of new neurological lesions post-TAVI. AIMS: We aimed to demonstrate the neuroprotective benefits of CO2 flushing in TAVI patients. METHODS: INTERCEPTavi is a single-centre, blinded, randomised controlled pilot trial that studied the effects of flushing TAVI valves with CO2 versus conventional saline on neurological outcomes post-TAVI, assessed using magnetic resonance imaging (MRI) and transcranial Doppler (TCD). Patients with aortic stenosis were randomised after obtaining vascular access. Periprocedural TCD assessed solid and gaseous emboli to the brain. Post-procedure, patients underwent brain MRI to detect lesions. Here, we report the primary outcome of feasibility, as well as the secondary MRI and mechanistic TCD outcomes. RESULTS: A total of 60 patients were recruited and randomised 1:1 to CO2 and saline flushing (TAVI-CO2) versus saline flushing only (TAVI-S). CO2 flushing significantly reduced the average number of lesions per patient (TAVI-CO2: 4 lesions/patient vs TAVI-S: 8.5 lesions/patient; p=0.031). The total infarct area was numerically lower in the TAVI-CO2 group (40.32 mm2 vs 93.20 mm2), although this did not reach statistical significance (p=0.111). Similarly, TCD showed fewer microembolic signals in the TAVI-CO2 arm, primarily due to a reduction in gaseous emboli, but this difference was not statistically significant (p=0.5). CONCLUSIONS: INTERCEPTavi is a pioneering, first-in-human randomised trial that demonstrated that CO2 flu
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Journal articleWang D, Lawrie A, Delgado San Martin J, 2026,
Pre-diagnostic comorbidity pathways are associated with the timing of pulmonary hypertension outcomes: a case control study
, BMC Pulmonary Medicine, ISSN: 1471-2466Background: Pulmonary hypertension (PH) is a life-threatening condition often diagnosed late due to non-specific symptoms and overlapping comorbidities with other cardiovascular and respiratory diseases. Although there have been advances in treatment, diagnostic delays are common, and patients are treated late in their disease course. Investigating the temporal ordering of recorded comorbidities may provide insight into diagnostic patterns associated with delayed PH recognition and adverse outcomes. Methods: We identified 2,727 PH patients from the UK Biobank cohort of 440,014 participants with diseases diagnoses, and sampled two demographics-matched cohorts of chronic obstructive pulmonary disease (COPD) and heart failure (HF) with the same number of patients as the PH cohort but were not diagnosed with PH. Employing process mining, a methodology originating from business process analysis to extract temporal patterns from event logs, the temporal diagnostic sequences of comorbidity combinations preceding PH diagnosis were compared to those sequences in patients who received a final diagnosis COPD or HF. We also assessed the relative risk of mortality given different combinations of comorbidities and the genetic correlation between comorbidities. Results: Patients diagnosed with PH had prior diagnoses of hypertension (58.1%), atrial fibrillation (31.2%), and heart failure (43.2%). Process mining revealed that the temporal order of cardiometabolic comorbidities influences the timing to diagnosis of PH, COPD and HF. Patients in which type 2 diabetes was diagnosed before systemic hypertension had received PH diagnosis 2 years and 9 months faster than the reverse sequence, where hypertension preceded diabetes. For patients with a final diagnosis of PH, HF and COPD, diagnostic sequences in which hypercholesterolemia was recorded before systemic hypertension and type 2 diabetes were associated with shorter median intervals to PH diagnosis. A sequence involving diabetes, h
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Journal articleSharma T, Fall T, Sayols-Baixeras S, et al., 2026,
Linking Lipidomics to Vulnerable Coronary Plaques: A PROSPECT II Substudy.
, Arterioscler Thromb Vasc Biol, Vol: 46BACKGROUND: Lipidomics, the comprehensive profiling of circulating lipid species, has emerged as a powerful tool to investigate metabolic alterations underlying coronary atherosclerosis. Understanding the mechanisms driving high-risk vulnerable plaque formation and progression to myocardial infarction remains a key therapeutic priority. This study investigates associations between circulating lipid metabolites and imaging-defined features of vulnerable coronary plaque. METHODS: Following revascularization, patients with myocardial infarction underwent 3-vessel coronary artery imaging with near-infrared spectroscopy and intravascular ultrasound to assess nonflow-limiting plaques for lipid core burden index and plaque burden. Multivariable models evaluated associations between 424 lipid metabolites in plasma, quantified by mass spectrometry, pan-coronary lipid, pan-coronary plaque burden, and high-risk vulnerable plaque measures (maximum lipid core burden index within any 4-mm segment across the entire lesion ≥324.7 and/or plaque burden ≥70%) in 877 patients. Findings were validated in the SCAPIS study (Swedish Cardiopulmonary Bioimage Study) using coronary computed tomography angiography-based measures of coronary artery calcium score and segment involvement score. RESULTS: We identified 156 significant associations (P<0.05) between lipid metabolites and coronary plaque characteristics across 39 metabolic pathways. Sphingomyelins were inversely associated with all plaque metrics, and 1-palmitoyl-2-oleoyl-GPE (glycero-3-phosphoethanolamine; 16:0/18:1), a phosphatidylethanolamine, was positively associated with all plaque metrics. After correcting for multiple testing, 27 lipid species across 7 pathways remained significant (q<0.05). The majority were linked to pan-coronary lipid burden, with the strongest inverse association observed for sphingomyelin d18:1/22:1, d18:2/22:0, and d16:1/24:1. Similar inverse patterns were seen for select dihydrosphingomyelin
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Journal articleSchmiedmayer P, Johnson A, Schuetz N, et al., 2026,
Design and rationale of the my heart counts cardiovascular health study: a large-scale, fully digital biobank, and randomized trial of large language model-driven coaching of physical activity.
, Am J Prev Cardiol, Vol: 28BACKGROUND: Cardiovascular disease remains the leading cause of global morbidity and mortality. The original My Heart Counts smartphone application demonstrated the feasibility of large-scale, fully digital recruitment and trial conduct, but was limited by platform exclusivity and the need for human experts to create text-based behavioral interventions. METHODS: The next-generation My Heart Counts smartphone application is a prospective, observational cohort study with an embedded randomized crossover trial, evaluating personalized text-based coaching prompts, available in both English and Spanish. All study and trial operations will be conducted via the My Heart Counts smartphone application, re-designed using the open-source Stanford Spezi framework to support iOS, with a planned Android release in 2027. The target enrollment is N = 15,000 adults across the United States and United Kingdom. The study establishes a comprehensive digital biobank by synthesizing passive mobile health data (steps, flights climbed, heart rate, sleep, workouts), raw sensor data (e.g., accelerometry), longitudinal clinical surveys, active tasks (6-minute walk test and 12-minute Cooper run test), electrocardiograms (ECG), and electronic health record (EHR) data integrated via HL7 FHIR protocols. The embedded trial evaluates the effect of text-based coaching prompts generated by a large language model (LLM) grounded in the Transtheoretical Model of Change on daily physical activity, as compared to generic prompts. PLANNED ANALYSIS: The primary endpoint of the randomized crossover trial is change in daily step count between LLM-driven and generic text-based intervention arms, analyzed using mixed-effects models. Secondary endpoints include change in mean active minutes and calorie burn over each intervention week. Other exploratory analyses include the changes in submaximal (6-minute walk test) and maximal (Cooper 12-minute run test) cardiorespiratory fitness, changes to sensor-derived biom
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Journal articlePruktanakul T, Lynham S, Chen H, et al., 2026,
ComparativeAnalysis of Data Processing Tools forMass Spectrometry Proteomics in Cardiovascular Research
, Journal of Proteome Research, ISSN: 1535-3893<jats:title>Abstract</jats:title> <jats:p>Mass spectrometry-based proteomics requires advanced data processing tools, yet most comparative studies have relied on noncardiovascular data sets or standard protein mixtures, limiting their relevance to cardiovascular research. We systematically compared three label-free data-dependent acquisition (DDA) tools (FragPipe, MaxQuant, and Proteome Discoverer) and five data-independent acquisition (DIA) tools (DIA-NN, DIA-Umpire, MSFragger-DIA, MaxDIA, and Spectronaut) using real-world cardiovascular tissue and blood-derived proteomics data sets. FragPipe and Spectronaut generally achieved the greatest quantitative proteome coverage among the evaluated DDA and DIA tools, respectively, particularly in cardiovascular tissue data sets, although tool rankings varied across sample types and proteome subsets. Despite differences in identification and quantification performance, peptide physicochemical characteristics were broadly similar across tools. Integration of complementary differential expression outputs increased differentially expressed protein detection in several data sets while maintaining agreement with the main results. These findings provide practical guidance for selecting data processing tools in cardiovascular proteomics and support the use of integrative approaches to maximize biological information from proteomics data sets.</jats:p>
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Journal articleYogeswaran A, Fünderich M, Wendlandt K, et al., 2026,
Angiotensin Converting Enzyme Inhibition and Mortality in Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD)
, Pulmonary Circulation, Vol: 16, ISSN: 2045-8932In 567 PH-COPD patients from the PVRI GoDeep Meta-Registry, ACE inhibitor use was associated with improved survival only in severe PH (PVR > 5 WU), supporting prospective trials targeting this high-risk subgroup.
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Journal articleKardys I, Mayr M, Mair J, et al., 2026,
Proteomics profiling for cardiovascular risk prediction: transforming clinical care.
, Eur Heart J Acute Cardiovasc Care, Vol: 15, Pages: 481-483 -
Journal articleAlharbi R, Keles M, Fernandez N, et al., 2026,
KLF6 activation marks an angiogenic and apoptosis resistant endothelial phenotype in pulmonary arterial hypertension
, Communications Biology, ISSN: 2399-3642 -
Journal articleBarallobre-Barreiro J, Mayr M, 2026,
Proteomic insights into bi-atrial remodelling in persistent atrial fibrillation.
, Cardiovasc Res, Vol: 122, Pages: 958-959 -
Journal articleLundby A, Van Eyk JE, Mayr M, et al., 2026,
Consensus statement on mass spectrometry-based proteomic analysis of cardiac tissue.
, Nat Cardiovasc Res, Vol: 5, Pages: 526-540Mass spectrometry-based cardiac proteomics provides direct molecular insight into cardiac physiology and disease. While plasma proteomics has advanced biomarker discovery, the analysis of cardiac tissue is essential for mechanistic understanding and therapeutic target identification; however, proteomic investigation of cardiac tissue faces unique challenges, including limited sample availability, regional heterogeneity, variability in collection and processing, and inconsistent reporting practices that hinder reproducibility and data integration. Here, we provide a practical framework for designing and conducting mass spectrometry-based proteomic studies of cardiac tissue and primary cardiac cells. We outline best practices and key considerations for sample handling, experimental design, data acquisition, quality control and statistical analysis. This guideline aims to support cardiac researchers in generating robust and reproducible proteomics datasets that advance our understanding of cardiac biology in both physiological and pathological contexts.
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Journal articlePericleous C, Strauss E, Arachchillage DJ, 2026,
Endothelial dysfunction in APS: advancing pathophysiological understanding to improve management.
, Curr Opin Immunol, Vol: 100Endothelial dysfunction (ED) is a hallmark of antiphospholipid syndrome (APS) driven by chronic antiphospholipid antibody (aPL) exposure. Beyond acute thrombotic events, ED contributes to atherosclerosis, vascular remodelling, stenosis and multi-organ manifestations, positioning the endothelium as a putative target for disease monitoring and therapeutic intervention. In this review, we integrate new experimental and clinical studies with emerging data presented at recent international meetings that advance our understanding of endothelial pathophysiology in APS. These studies reveal novel APS vascular endotypes and convergence between aPL-driven endothelial thromboinflammation, endothelial-to-mesenchymal transition, extracellular matrix remodelling and aberrant cell growth pathways across arterial, venous and capillary territories, and multiple organs. We discuss evolving approaches to assess endothelial health, including circulating biomarkers, endothelial colony-forming cells, and non-invasive functional and imaging-based tools. Finally, we highlight the need to integrate early detection, aggressive cardiovascular risk modification and precision medicine to mitigate ED and improve long-term outcomes in APS.
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Journal articleNaser J, Fogell NA, Patel M, et al., 2026,
Experimental comparisons of optical coherence tomography-based versus angiography-based time-averaged wall shear stress estimations.
, Int J Cardiovasc Imaging, Vol: 42, Pages: 1029-1043An approach to rapid simulation of time-averaged wall shear stress (TAWSS) on 3D geometries created from 3D Quantitative Coronary Angiography (3D-QCA) methodology has been developed, which enables rapid computational fluid dynamic (CFD) shear stress simulation. We compared TAWSS estimated from 3D-QCA-CFD with optical coherence tomography (OCT)-based CFD simulations in coronary arteries. 15 normal and 5 stenotic coronary arteries in instrumented minipigs were studied. 3D arterial geometries were reconstructed from 3D-QCA and OCT using common centrelines and matched axial positions. Identical boundary conditions were used for both methods through directly measured vessel-specific inlet blood velocities. TAWSS was calculated for axially matched segments (n = 80 for normal arteries; n = 160 for stenotic arteries) and in 3 mm/60° sectors. Mean TAWSS simulation times for 3D-QCA and OCT-based CFD were 17.8 min and ~ 1.5 h respectively. There were significant but numerically small differences in TAWSS for normal arteries (-0.21 ± 0.64 Pa [95%CI -1.04,1.46], p < 0.001), and no significant difference for stenotic arteries (-0.39 ± 3.04 Pa [95%CI -6.35, 5.56], p = 0.25). Axial TAWSS profiles along vessel lengths were similar between the two methods. There is a trend of underestimation by 3D-QCA at higher values of TAWSS compared with OCT, due to differences in geometry dimensions. Similar spatial distributions of TAWSS in both normal and stenotic arteries were observed from co-registered TAWSS maps. This study suggests that 3D-QCA-based TAWSS is feasible in both normal and stenotic arteries and that further clinical evaluation of rapid TAWSS from 3D-QCA is warranted, which may facilitate clinical adoption of TAWSS assessment.
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Journal articleJiang W, Lynam E, Delafosse J, et al., 2026,
ZONAB Regulates DNA Methylation, Mitochondrial Function, and Entry into Cell Senescence of Endothelial Cells.
, Cells, Vol: 15Regulation of the endothelial stress response is important for blood vessel homeostasis and angiogenesis, processes disrupted in common vascular diseases and ageing. Here, we discovered that the Y-box factor ZONAB (ZO-1-associated nucleic acid binding protein; YBX3), a gene associated with risk loci for severe vascular disorders, regulates endothelial homeostasis and angiogenesis. By combining cell-based assays with primary endothelial cells and genome-wide expression and methylation measurements, we found that ZONAB depletion results in mitochondrial deregulation, increased reactive oxygen species, and a defective oxidative stress response, which correlates with increased promoter methylation of cell cycle genes. ZONAB depletion triggered cellular senescence via a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent pathway, which was attenuated by PIK3 inhibitors, an antioxidant, or by drugs targeting mitochondrial function or fragmentation. Thus, our results reveal that ZONAB repression in endothelial cells leads to genome-wide changes in gene expression and DNA methylation, regulating endothelial proliferation and inflammation, as well as mitochondrial deregulation to promote cellular senescence. Hence, ZONAB supports endothelial homeostasis and may play a role in vascular health.
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Journal articleSamaranayake CB, Niglas M, Baxan N, et al., 2026,
Hemodynamic and metabolomic responses to infusion of GLP-1 agonist exenatide in pulmonary arterial hypertension
, JCI Insight, Vol: 11, ISSN: 2379-3708Preclinical studies suggest beneficial effects of GLP-1 agonists in pulmonary arterial hypertension (PAH). This first-in-disease study evaluated acute hemodynamic effects of GLP-1 agonist, exenatide administered i.v. in patients with idiopathic PAH and CTEPH as well as in a PAH rodent model. Seventeen patients (9 idiopathic PAH) received an exenatide infusion during right heart catheterization, which included multisite sampling for circulating metabolites. Acute effects of exenatide were also assessed by cardiac magnetic resonance imaging in monocrotaline (MCT) PAH and control rats. In the clinical study, exenatide was well tolerated, reduced mean pulmonary artery pressure (45 ± 15 mmHg versus 40 ± 18 mmHg), and improved cardiac index (2.1 ± 0.6 L/min versus 2.4 ± 0.9 L/min/m2) and pulmonary vascular resistance (7.8 ± 8.0 WU versus 5.9 ± 5.0 WU) across all patients. Right ventricular (RV) contractility and afterload improved in a subset of patients undergoing pressure-volume measurements. In an exploratory metabolomics analysis, 47 metabolite levels changed after exenatide infusion, predominantly in free fatty acid pathways. Six metabolites with prognostic relevance in PAH within myocardial glycolytic and lipid oxidation pathways were also altered after exenatide. In MCT rats, exenatide improved RV stroke-volume, RV ejection fraction, and RV-arterial coupling. These findings support the further evaluation of exenatide within chronic studies as a potentially novel pulmonary vasodilator therapy.
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