Transcription factors in the pathogenesis of pulmonary arterial hypertension—Current knowledge and therapeutic potential

Pulmonary arterial hypertension (PAH) is a disease characterized by elevated pulmonary vascular resistance and pulmonary artery pressure. Mortality remains high in severe cases despite significant advances in management and pharmacotherapy. Since currently approved PAH therapies are unable to significantly reverse pathological vessel remodeling, novel disease-modifying, targeted therapeutics are needed. Pathogenetically, PAH is characterized by vessel wall cell dysfunction with consecutive remodeling of the pulmonary vasculature and the right heart. Transcription factors (TFs) regulate the process of transcribing DNA into RNA and, in the pulmonary circulation, control the response of pulmonary vascular cells to macro- and microenvironmental stimuli. Often, TFs form complex protein interaction networks with other TFs or co-factors to allow for fine-tuning of gene expression. Therefore, identification of the underlying molecular mechanisms of TF (dys-)function is essential to develop tailored modulation strategies in PAH. This current review provides a compendium-style overview of TFs and TF complexes associated with PAH pathogenesis and highlights their potential as targets for vasculoregenerative or reverse remodeling therapies

Polycomb Repressive Complex 2 and KRYPTONITE regulate pathogen-induced programmed cell death in Arabidopsis

The Polycomb Repressive Complex 2 (PRC2) is well-known for its role in controlling developmental transitions by suppressing the premature expression of key developmental regulators. Previous work revealed that PRC2 also controls the onset of senescence, a form of developmental programmed cell death (PCD) in plants. Whether the induction of PCD in response to stress is similarly suppressed by the PRC2 remained largely unknown. In this study, we explored whether PCD triggered in response to immunity- and disease-promoting pathogen effectors is associated with changes in the distribution of the PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) modification in Arabidopsis thaliana. We furthermore tested the distribution of the heterochromatic histone mark H3K9me2, which is established, to a large extent, by the H3K9 methyltransferase KRYPTONITE, and occupies chromatin regions generally not targeted by PRC2. We report that effector-induced PCD caused major changes in the distribution of both repressive epigenetic modifications and that both modifications have a regulatory role and impact on the onset of PCD during pathogen infection. Our work highlights that the transition to pathogen-induced PCD is epigenetically controlled, revealing striking similarities to developmental PCD

The Endothelial ADMA/NO Pathway in Hypoxia-Related Chronic Respiratory Diseases

Since its discovery, many adhere to the view that asymmetric dimethylarginine (ADMA), as an inhibitor of the synthesis of nitric oxide (NO), contributes to the pathogenesis of various diseases. Particularly, this is evident in disease of the cardiovascular system, in which endothelial dysfunction results in an imbalance between vasoconstriction and vasodilatation. Even if increased ADMA concentrations are closely related to an endothelial dysfunction, several studies pointed to a potential beneficial effect of ADMA, mainly in the context of angioproliferative disease such as cancer and fibrosis. Antiproliferative properties of ADMA independent of NO have been identified in this context. In particular, the regulation of ADMA by its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) is the object of many studies. DDAH is discussed as a promising therapeutic target for the indirect regulation of NO. In hypoxia-related chronic respiratory diseases, this controversy discussion of ADMA and DDAH is particularly evident and is therefore subject of this review

Genetic evidence for a causative effect of airflow obstruction on left ventricular filling: a Mendelian randomisation study

Background!#!Observational studies on the general population have suggested that airflow obstruction associates with left ventricular (LV) filling. To limit the influence of environmental risk factors/exposures, we used a Mendelian randomisation (MR) approach based on common genetic variations and tested whether a causative relation between airflow obstruction and LV filling can be detected.!##!Methods!#!We used summary statistics from large genome-wide association studies (GWAS) on the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) measured by spirometry and the LV end-diastolic volume (LVEDV) as assessed by cardiac magnetic resonance imaging. The primary MR was based on an inverse variance weighted regression. Various complementary MR methods and subsets of the instrument variables were used to assess the plausibility of the findings.!##!Results!#!We obtained consistent evidence in our primary MR analysis and subsequent sensitivity analyses that reducing airflow obstruction leads to increased inflow to the LV (odds ratio [OR] from inverse variance weighted regression 1.05, 95% confidence interval [CI] 1.01-1.09, P = 0.0172). Sensitivity analyses indicated a certain extent of negative horizontal pleiotropy and the estimate from biased-corrected MR-Egger was adjusted upward (OR 1.2, 95% CI 1.09-1.31, P < 0.001). Prioritisation of single genetic variants revealed rs995758, rs2070600 and rs7733410 as major contributors to the MR result.!##!Conclusion!#!Our findings indicate a causal relationship between airflow obstruction and LV filling in the general population providing genetic context to observational associations. The results suggest that targeting (even subclinical) airflow obstruction can lead to direct cardiac improvements, demonstrated by an increase in LVEDV. Functional annotation of single genetic variants contributing most to the causal effect estimate could help to prioritise biological underpinnings

Residual risk identified in routine noninvasive follow-up assessments in pulmonary arterial hypertension

Background The 2022 ESC/ERS guidelines on pulmonary hypertension recommend noninvasive risk assessments based on three clinical variables during follow-up in patients with pulmonary arterial hypertension (PAH). We set out to test whether residual risk can be captured from routinely measured noninvasive clinical variables during follow-up in PAH. Methods We retrospectively studied 298 incident PAH patients from a German pulmonary hypertension centre who underwent routine noninvasive follow-up assessments including exercise testing, echocardiography, electrocardiography, pulmonary function testing and biochemistry. To select variables, we used least absolute shrinkage and selection operator (LASSO)-regularised Cox regression models. Outcome was defined as mortality or lung transplant after first follow-up assessment. Results 12 noninvasive variables that were associated with outcomes in a training sub-cohort (n=208) after correction for multiple testing entered LASSO modelling. A model combining seven variables discriminated 1-year (area under the curve (AUC) 0.83, 95% confidence interval (CI) 0.68–0.99, p=8.4×10−6) and 3-year (AUC 0.81, 95% CI 0.70–0.92, p=2.9×10−8) outcome status in a replication sub-cohort (n=90). The model's discriminatory ability was comparable to that of the guideline approach in the replication sub-cohort. From the individual model components, World Health Organization functional class, 6-min walking distance and the tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure (TAPSE/sPAP) ratio were sensitive to treatment initiation. Addition of TAPSE/sPAP ratio to the guideline approach numerically increased its ability to discriminate outcome status. Conclusion Our real-world data suggest that residual risk can be captured by noninvasive clinical procedures during routine follow-up assessments in patients with PAH and highlights the potential use of echocardiographic imaging to refine risk assessment

Clinical phenotyping of plasma thrombospondin-2 reveals relationship to right ventricular structure and function in pulmonary hypertension

Background Converging evidence from proteogenomic analyses prioritises thrombospondin-2 (TSP2) as a potential biomarker for idiopathic or heritable pulmonary arterial hypertension (PAH). We aimed to assess TSP2 levels in different forms of pulmonary hypertension (PH) and to define its clinical phenotype. Methods Absolute concentrations of TSP2 were quantified in plasma samples from a prospective single-centre cohort study including 196 patients with different forms of PH and 16 disease controls (suspected PH, but normal resting pulmonary haemodynamics). In an unbiased approach, TSP2 levels were related to 152 clinical variables. Results Concentrations of TSP2 were increased in patients with PH versus disease controls (p<0.001 for group comparison). The discriminatory ability of TSP2 levels to distinguish between patients and controls was superior to that of N-terminal pro-brain natriuretic peptide (p=0.0023 for comparison of areas under the curve). Elevation of TSP2 levels was consistently found in subcategories of PAH, in PH due to lung disease and due to left heart disease. Phenotypically, TSP2 levels were robustly related to echocardiographic markers that indicate the right ventricular (RV) response to chronically increased afterload with increased levels in patients with impaired systolic function and ventriculoarterial uncoupling. Focusing on PAH, increased TSP2 levels were able to distinguish between adaptive and maladaptive RV phenotypes (area under the curve 0.87, 95% CI 0.76–0.98). Interpretation The study indicates that plasma TSP2 levels inform on the presence of PH and associate with clinically relevant RV phenotypes in the setting of increased afterload, which may provide insight into processes of RV adaptability

N-Terminal Pro-Brain Natriuretic Peptide Is a Useful Prognostic Marker in Patients with Pre-Capillary Pulmonary Hypertension and Renal Insufficiency

<div><p>N-terminal pro-brain natriuretic peptide (NT-proBNP) is a routinely used prognostic parameter in patients with pre-capillary pulmonary hypertension (PH). As it accumulates in the presence of impaired renal function, the clinical utility of NT-proBNP in PH patients with concomitant renal insufficiency remains unclear. In a retrospective approach, patients with pre-capillary PH (group I or IV) and concomitant renal insufficiency at time of right heart catheterization (glomerular filtration rate (GFR) ≤60 ml/min/1.73 m²) were identified out of all prevalent pre-capillary PH patients treated at a single center. Forty patients with renal insufficiency (25.8%) were identified and matched regarding hemodynamic parameters with a control group of 56 PH patients with normal renal function (GFR >60 ml/min/1.73 m²). Correlations of NT-proBNP levels with hemodynamic and prognostic parameters (time to clinical worsening and overall survival) were assessed. Overall, GFR correlated inversely with NT-proBNP and had the strongest influence on NT-proBNP levels in a stepwise multiple linear regression model including hemodynamic parameters and age (r² = 0.167). PH patients with renal insufficiency had significant higher levels of NT-proBNP (median: 1935 ng/l vs. 573 ng/l, p = 0.001). Nevertheless, NT-proBNP correlated with invasive hemodynamic parameters in these patients. Using higher cut-off values than in patients with preserved renal function, NT-proBNP levels were significantly associated with time to clinical worsening (>1660 ng/l, p = 0.001) and survival (>2212 ng/l, p = 0.047) in patients with renal insufficiency. Multivariate Cox’s proportional hazards analysis including established prognostic parameters, age and GFR confirmed NT-proBNP as an independent risk factor for clinical worsening in PH patients with renal insufficiency (hazard ratio 4.8, p = 0.007). Thus, in a retrospective analysis we showed that NT-proBNP levels correlated with hemodynamic parameters and outcome regardless of renal function. By using higher cut-off values, NT-proBNP seems to represent a valid clinical marker even in PH patients with renal insufficiency.</p></div

Patients’ characteristics.

<p>Data are presented as mean ± SD or numbers.</p><p>Comparison of means between GFR-groups are performed by Student’s T, Mann-Whitney-U^& or Chi-Square test^§. CTD = connective tissue disease. ^# Other includes HIV, porto-pulmonary hypertension and congenital heart diseases.</p