This review presents an overview of the regulation, function, disease-relevance and pharmacological regulation of the critical endothelial transcription factors KLF2/4 in vasculature. The regulatory mechanisms of KLF2/4 expression and activity in vascular endothelium in response to hemodynamic forces and biochemical stimuli are depicted. The functional effects mediated by direct or indirect target genes of KLF2/4 in endothelial cells are systematically summarized. The contributory roles that dysregulated KLF2/4 play in relevant cardiovascular pathologies, such as atherosclerotic vascular lesions, pulmonary arterial hypertension and vascular complications of diabetes were reviewed. Moreover, this review also discusses the pharmacological regulation of KLF2/4 by drugs used in clinics and therapeutic possibility by directly targeting these two transcription factors for treating atherosclerotic cardiovascular diseases. Finally, prospective opinions on the gaps in disclosing novel vascular function mediated by KLF2/4 and future research needs are expressed.

Pulmonary arterial hypertension (PAH) is one of the most severe pulmonary diseases. Although combination therapies of the key drugs have improved survival rates, unmet needs remain in its management. We examined the effects of cyclopamine, a Hedgehog (HH) signaling inhibitor, as a potential novel therapeutic approach for PAH. C57BL/6J male mice were exposed to 10% oxygen for 3 weeks to induce pulmonary hypertension. One week after hypoxia exposure, these mice were treated with cyclopamine or vehicle. Cyclopamine significantly attenuated right ventricular (RV) systolic pressure (H + C: 31 mmHg vs. H: 38 mmHg, p < 0.01) and RV hypertrophy (H + C: 0.28 vs. H: 0.37, p < 0.01). The fully muscularized small pulmonary arteries significantly decreased with cyclopamine (H + C: 30% vs. H: 80%, p < 0.01), suggesting a mediation by vascular remodeling inhibition. In vitro, human pulmonary arterial smooth muscle cells (HPASMC) exposed to hypoxia revealed that the inhibitory action of cyclopamine was limited to hypoxia-promoted cell proliferation. In single-cell RNA sequencing analysis of mice lungs treated with cyclopamine, the signaling pathways of vascular smooth muscle contraction and cGMP-PKG, that is, key regulators in PAH development through vascular remodeling, were suppressed in cells with the characteristics of vascular endothelial and smooth muscle cells. RNA sequencing analysis of hypoxia-exposed hPASMCs revealed that the pathways related to extracellular matrix regulation were particularly recovered. Our animal model-based data revealed that HH signaling inhibition would improve PAH development by suppressing pulmonary vascular remodeling.

Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease driven by vascular remodeling, right ventricular (RV) dysfunction, and metabolic and inflammatory dysregulation. Current therapies primarily target vasodilation to relieve symptoms but do not reverse disease progression. The recent approval of sotatercept, which modulates BMP/TGF-β signaling, marks a shift toward anti-remodeling therapies. Building on this, recent preclinical advances have identified promising therapeutic targets and potentially disease-modifying treatments.

This review synthesizes the evolving preclinical landscape of emerging PAH therapeutic targets and drugs, highlighting innovative approaches aimed at addressing the underlying mechanisms of disease progression. Additionally, we discuss novel therapeutic strategies under development.

Recent advances in PAH research have identified novel therapeutic targets beyond vasodilators, including modulation of BMP/TGF-β signaling, metabolic programs, epigenetics, cancer-related signaling, the extracellular matrix, and immune pathways, among others. Sotatercept represents a significant advance in therapies that go beyond vasodilation, and long-term safety, efficacy, and durability are being assessed. Future treatment strategies will focus on precision approaches, noninvasive technologies, and regenerative biology to improve outcomes and reverse vascular remodeling.

Targeting ubiquitin E3 ligases is therapeutically attractive; however, the absence of an active-site pocket impedes computational approaches for identifying inhibitors. In a large, unbiased biochemical screen, we discover inhibitors that bind a cryptic cavity distant from the catalytic cysteine of the homologous to E6-associated protein C terminus domain (HECT) E3 ligase, SMAD ubiquitin regulatory factor 1 (SMURF1). Structural and biochemical analyses and engineered escape mutants revealed that these inhibitors restrict an essential catalytic motion by extending an α helix over a conserved glycine hinge. SMURF1 levels are increased in pulmonary arterial hypertension (PAH), a disease caused by mutation of bone morphogenetic protein receptor-2 (BMPR2). We demonstrated that SMURF1 inhibition prevented BMPR2 ubiquitylation, normalized bone morphogenetic protein (BMP) signaling, restored pulmonary vascular cell homeostasis, and reversed pathology in established experimental PAH. Leveraging this deep mechanistic understanding, we undertook an in silico machine-learning-based screen to identify inhibitors of the prototypic HECT E6AP and confirmed glycine-hinge-dependent allosteric activity in vitro. Inhibiting HECTs and other glycine-hinge proteins opens a new druggable space.

Adipocyte dysfunction contributes to lipotoxicity and cardiometabolic diseases. Bone morphogenetic protein 4 (BMP4) is expressed in white adipocytes and remodels white adipose tissue, while liver-derived BMP9, a key circulating BMP, influences adipocyte lipid metabolism. The gene sets regulated by BMP4 and BMP9 signalling in mature adipocytes remain unclear. Here, we directly compare BMP4 and BMP9 signalling in mature brown and white adipocytes. While both BMPs showed comparable potency across adipocyte types, RNA sequencing analysis revealed extensive gene regulation, with many more differentially expressed genes and suppression of critical metabolic pathways in white adipocytes. Although BMP4 and BMP9 induced inhibitors of BMP and GDF signalling in both adipocytes, they selectively upregulated several TGF-β family receptors and BMP4 expression only in white adipocytes. These findings underscore a central role of BMP signalling in adipocyte homeostasis and suggest both BMP4 and BMP9 as regulators of white adipocyte plasticity with potential therapeutic implications.

Sotatercept binds free activins by mimicking the extracellular domain of the activin receptor type IIA (ACTRIIA). Additional ligands are BMP/TGF-beta, GDF8, GDF11 and BMP10. The binding with activins leads to the inhibition of the signalling pathway and the deactivation of the bone morphogenic protein (BMP) receptor type 2. In this way, sotatercept activates an antiproliferative signalling to the cells of the pulmonary arteries and arterioles with the aim of rebalancing the proliferative and antiproliferative pathway that characterizes the pulmonary arterial hypertension (PAH). Sotatercept is indicated for the treatment of group 1 PAH in combination with drugs that act through the endothelin receptor, nitric oxide or prostacyclin. Its effects, demonstrated in the STELLAR study, are the improvement of exercise capacity and the FC-WHO functional class, together with the reduction of the risk of clinical worsening events. In addition to its antiremodeling effects on the pulmonary circulation, sotatercept has several haematological effects that could suggest its use in the treatment of some blood disorders other than PAH. In this review, we will discuss the effects of the drug on PAH and in parallel provide an in-depth overview of its application in haematological disorders, focusing on clinical and preclinical studies.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe condition resulting from unresolved thrombi in the pulmonary arteries, leading to increased pulmonary vascular resistance and right heart failure. Currently, the scarcity of clinically relevant animal models of CTEPH significantly hampers mechanistic studies and drug development.

This study aimed to establish a rat model of CTEPH by combining splenectomy with thrombus injection, simulating key clinical risk factors associated with the disease. Rats underwent splenectomy and subsequent intravenous administration of thrombi, followed by hemodynamic and histological measurements as well as lung tissue RNA sequencing.

Splenectomized rats exhibited significant increases in platelets and delayed thrombolysis. Five weeks after splenectomy and thrombus injection, the rats exhibited thrombus retention in large pulmonary arteries, increased right ventricular systolic pressure, and pulmonary vascular remodeling, which were characteristic of CTEPH. Transcriptomic analysis revealed increased expression of inflammatory cytokines Ccl2 and Ccl3, as well as the B cell marker Cd79a, which was confirmed as an increase in CD79A+ B cells in the lung tissue.

Overall, this novel approach of combining splenectomy with thrombus injection provides a clinically relevant model for studying CTEPH pathophysiology and evaluating potential therapeutic interventions.

Pulmonary arterial hypertension is a progressive disease associated with significant morbidity and mortality. Sotatercept is a first-in-class activin signalling inhibitor that acts to restore the balance between the growth-promoting and growth-inhibiting signalling pathways.

This post hoc, exploratory, pooled analysis combines data from the double-blind placebo periods of the phase 2 PULSAR (NCT03496207) and phase 3 STELLAR (NCT04576988) studies. Both studies were international, multicentre, randomised, double-blind, placebo-controlled trials in patients with pulmonary arterial hypertension. Efficacy and safety parameters common to both studies were analysed.

A total of 429 patients were randomised and treated; 237 received sotatercept and 192 received placebo. Adding sotatercept to background pulmonary arterial hypertension therapy for 24 weeks improved exercise capacity (as assessed by 6-min walk distance), pulmonary vascular resistance and World Health Organization functional class, and delayed time to first occurrence of death or clinical worsening event. There were clinically important reductions in both pulmonary and right heart pressures; improvements in right ventricle size during both systole and diastole; and enhancements in right ventricle contractility and right ventricular-pulmonary artery coupling. The number of patients who experienced at least one adverse event of interest or special interest (increased haemoglobin, thrombocytopenia, bleeding events (mostly epistaxis), increased blood pressure and telangiectasia) was higher in the sotatercept group than the placebo group.

This pooled analysis confirms that sotatercept delivers therapeutic benefit across a range of efficacy end-points and has favourable safety in patients with pulmonary arterial hypertension. Increased duration of follow-up will provide further insight into long-term outcomes of sotatercept in patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) exhibits significant gender differences in prognosis, with male patients typically showing worse outcomes than females. These disparities may stem from differences in androgen receptor expression and activity. Clinical studies suggest that the androgen receptor plays a crucial role in the pathophysiology of PAH, influencing disease progression and treatment response. Despite the lack of targeted therapies for PAH, these findings have spurred investigations into the potential therapeutic role of androgen receptors. This study explores the role of androgen receptors in PAH and evaluates their therapeutic potential.

PAH was induced in rats via intraperitoneal injection of monocrotaline (MCT). Following model establishment, Enzalutamide was administered every 3 days at 10 mg/kg once for a total of 7 times (21 days). A mouse model of PAH was developed by subcutaneously injecting SU5416 and exposing the mice to hypoxia. Androgen receptor knockout (AR-/-) mice were also utilized to investigate the role of androgen receptors in disease progression. Key indicators were compared across groups. The in vivo mechanisms through which androgen receptors influence PAH were examined in both rat and mouse models. Additionally, mouse pulmonary artery endothelial cells (PAECs) were cultured under hypoxic conditions to create an in vitro model of PAH, facilitating further investigation into the role of androgen receptors in disease pathogenesis.

Compared to the normal group, the model group exhibited significantly increased androgen receptor expression in rats, mice, and mPAECs. This was accompanied by pronounced pulmonary artery wall thickening, right ventricular hypertrophy, pulmonary fibrosis, elevated pulmonary artery pressure, and a reduced level of apoptosis both in vivo and in vitro. Furthermore, activation of the Notch3/Hes5 signaling pathway was observed. However, treatment with androgen receptor inhibitors or gene knockout significantly ameliorated these pathological changes. Apoptosis levels increased both in vivo and in vitro, and the activation of the Notch3/Hes5 signaling pathway was effectively inhibited.

Our findings suggest that in both animal models and the hypoxic mPAECs, inhibition of androgen receptor expression leads to increased apoptosis via suppression of the Notch3/Hes5 signaling pathway. This mechanism likely contributes to the therapeutic effects observed, providing insights for potential treatment strategies targeting androgen receptors in pulmonary arterial hypertension.

Abdominal aortic aneurysm (AAA) is one of the most common fatal macrovascular diseases worldwide which pathogenesis is still not well clarified. In this study, we systematically investigated the alternations of endothelial cell (ECs) functions and phenotypes by single-cell RNA sequencing in angiotensin (Ang) II-induced AAA mice models.

According to 10 × single-cell sequencing analysis, we revealed that ECs inflammation and endothelial-mesenchymal transition (EndoMT) were involved in the progress of Ang II-induced AAA. Three types of ECs, including Mature ECs (uninjured ECs), EndoMT ECs and Injury & inflammation ECs successively emerged during the progression of AAA. By using pseudotime-trajectory analysis, we speculated bone morphogenetic protein 4 (BMP4) as a candidate gene, participating in Ang II-induced AAA by regulating EndoMT and vascular inflammation. We found that inhibition of BMP4 ameliorated EndoMT and vascular inflammation in Ang II-induced AAA in vivo. In addition, we found that exogenous BMP4 directly promoted the phenotypic transition, inflammation, cell migration and invasion of mouse aortic endothelial cells via PI3K/AKT/mTOR pathways in vitro. Finally, Protein-protein interaction (PPI) analysis and co-immunoprecipitation (Co-IP) revealed that biglycan (BGN) directly combined with BMP4 and promoted the conversion of EndoMT.

Our findings firstly revealed a critical role of BMP4 in AAA progression, which promoted disease progression by inducing EndoMT and reprogramming ECs from anti-inflammatory to proinflammatory phenotype.

Activin-A is elevated in pulmonary arterial hypertension (PAH) patients, and reportedly suppresses BMPR-II. This suggests one mechanism of action for PAH drug, sotatercept, an activin-ligand trap. However, we were unable to confirm that activin-A reduces BMPR-II in pulmonary endothelial cells. Thus, it seems unlikely that sotatercept influences BMPR-II or PAH via this mechanism.

This analysis examined the effects of the activin signaling inhibitor, sotatercept, in pulmonary arterial hypertension (PAH) subgroups stratified by baseline cardiac index (CI).

Pooled data from PULSAR (N = 106; NCT03496207) and STELLAR (N = 323; NCT04576988) were analyzed using 2 different CI thresholds, <2.0 and ≥2.0 liter/min/m2 as well as <2.5 and ≥2.5 liter/min/m2. Median changes from baseline at week 24 were evaluated using Hodges-Lehmann estimator and least squares (LS) means, with 95% confidence intervals and p-values (significance: p = 0.05). Categorial endpoints and time-to-clinical worsening were analyzed by Cochran-Mantel-Haenszel and Cox model respectively.

Of 429 participants, 51 had CI <2.0 and 378 ≥2.0 liter/min/m2, while 179 had CI <2.5 and 250 ≥2.5 liter/min/m2. Sotatercept significantly improved median 6-minute walk distance (range: 33.9 to 63.7 m: p < 0.001), pulmonary vascular resistance (range: -202.8 to -395.4 dyn•s•cm-5; p ≤ 0.002), and N-terminal pro-B-type natriuretic peptide (range: -317.3 to -1,041.2 pg/ml; p < 0.001) across subgroups. LS means showed reductions in pulmonary and right atrial pressures, decreased right ventricular size, and improved tricuspid annular plane systolic excursion/systolic pulmonary artery pressure. Sotatercept delayed time to first occurrence of death or a worsening event for CI ≥2.5 (hazard ratio [HR] 0.12; p < 0.001), ≥2.0 (HR 0.13; p < 0.001), and <2.5 (HR 0.21; p < 0.001) liter/min/m2. Improvements were observed in WHO functional class (all p < 0.050) and ESC/ERS risk scores (all p < 0.001).

Sotatercept demonstrated consistent efficacy and safety across CI subgroups, supporting its use in PAH patients irrespective of baseline cardiac hemodynamics.

High-altitude pulmonary hypertension (HAPH) is a condition characterized by elevated pulmonary arterial pressure exceeding normal physiological values, resulting from a combination of high-altitude low-pressure, hypoxic environments, genetic susceptibility, immune dysfunction, and neurogenic disturbances. This condition predominantly manifests as right heart failure, severely impacting quality of life and life expectancy. Macrophages, as one of the most prevalent innate immune cells, have been increasingly recognized for their crucial role in the pathogenesis of HAPH. The low-pressure and hypoxic environment, along with other etiological factors, lead to metabolic abnormalities in tissue cells and the microenvironment. This results in increased secretion of chemokines, cytokines, and growth factors in the microenvironment, which promote the proliferation of tissue-resident macrophages and the differentiation of monocytes recruited from the blood into macrophages. This exacerbates the inflammatory cascade, further promoting cell proliferation, tissue repair, and inhibition of apoptosis. These processes contribute to the migration and proliferation of pulmonary arterial smooth muscle cells, endothelial cells, and fibroblasts, leading to vascular remodeling and ultimately the development of pulmonary arterial hypertension. This review examines the role of macrophage-mediated immune responses in high-altitude pulmonary arterial hypertension, with a focus on hypoxia as a key feature.

Primary pulmonary hypertension (PPH), now known as pulmonary arterial hypertension (PAH), has induced significant treatment breakthroughs in the past decade. Treatment has focused on improving patient survival and quality of life, and delaying disease progression. Current therapies are categorized based on targeting different pathways known to contribute to PAH, including endothelin receptor antagonists (ERAs), phosphodiesterase-5 inhibitors (PDE-5 inhibitors), prostacyclin analogs, soluble guanylate cyclase stimulators, and activin signaling inhibitors such as Sotatercept. The latest addition to treatment options is soluble guanylate cyclase stimulators, such as Riociguat, which directly stimulates the nitric oxide pathway, facilitating vasodilation. Looking to the future, advancements in PAH treatment focus on precision medicine involving the sub-stratification of patients through a deep characterization of altered Transforming Growth Factor-β(TGF-β) signaling and molecular therapies. Gene therapy, targeting specific genetic mutations linked to PAH, and cell-based therapies, such as mesenchymal stem cells, are under investigation. Besides prevailing therapies, emerging PH treatments target growth factors and inflammation-modulating pathways, with ongoing trials assessing their long-term benefits and safety. Hence, this review explores current therapies that delay progression and improve survival, as well as future treatments with curative potential.

Pulmonary Arterial Hypertension (PAH) is a complex and progressive disease characterized by elevated pulmonary vascular resistance and right heart failure. Current therapies primarily focus on pulmonary vasodilation; however, novel approaches that target the underlying pathophysiological mechanisms-such as TGF-β signalling, epigenetic alterations, growth factors, inflammation, and extracellular matrix remodelling-are promising alternatives for improving treatment outcomes. This is a review of recent advances in the development of innovative therapeutic strategies for PAH. The first section of this paper explores approaches targeting TGF-β signalling, both acting directly on receptors through drugs like Sotatercept and exogenous BMP9, and indirectly, inhibiting the degradation of key receptors, such as BMPR2. Subsequent sections describe treatments that target epigenetic regulators, e.g. poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors and direct BRD4 antagonists, tyrosine kinase inhibitors (Seralutinib), and therapies aimed at inflammation, such as IL-6 inhibitors, CD-20 inhibitors, and monoclonal antibodies that prevent macrophage migration. Finally, strategies that target the serotonin pathway, and other metabolic and hormonal pathways are described. This review includes both preclinical and clinical trial data that support efficacy, safety and the future potential of such therapies. Collectively, these therapeutic approaches can be valuable in treating PAH by targeting multiple aspects of its pathogenesis, potentially resulting in improved clinical outcomes for patients affected by this debilitating, life-limiting condition.

Objective: The objective of the study is to review the characteristics, efficacy, safety, and clinical relevance of sotatercept in pulmonary arterial hypertension (PAH). Data Sources: A literature search containing search terms related to sotatercept and PAH was conducted. Embase via Elsevier, MEDLINE via Ovid, the medRxiv preprint server, Cochrane Library CENTRAL trials registry, and ClinicalTrials.gov were searched from inception through October 31, 2024. The package insert was utilized to obtain drug information and additional data. Study Selection and Data Extraction: Phase II-III clinical trials investigating sotatercept for PAH were included. Articles written in English were extracted while animal studies and phase I clinical trials were excluded. Data Synthesis: In patients with WHO Group 1, functional class II-III PAH, adding sotatercept to background therapy increased 6-minute walk distance in phase II-III trials. Pooled analysis from PULSAR (phase II) and STELLAR (phase III) showed improvements in pulmonary vascular resistance and NT-proBNP. Exploratory data from PULSAR revealed that BMPR2 genetic variant status was not associated with significant differences in treatment effects. SPECTRA (phase IIb) demonstrated improved right ventricular structure and function. Interim analysis from SOTERIA showed that treatment effects persist at 1 year. Conclusions: Sotatercept is a viable add-on therapy for patients with PAH Group 1 and functional class II-III. Additional data are needed to assess long-term outcomes among treatment-naïve patients and those with the most severe symptomatology.

Pulmonary Arterial Hypertension (PAH) is an uncommon condition with high mortality. It is an underrecognized condition both in developing and developed countries, especially in developing countries, due to a lack of advanced healthcare facilities and resources for timely diagnosis. More than half of the individuals diagnosed with PAH live less than five years after diagnosis. In recent years, tremendous advancements have been made in diagnostic and therapeutic strategies for PAH patients. Phosphodiesterase 5 (PDE5) inhibitors, endothelin receptor antagonists, and prostacyclin inhibitors in various forms (oral, inhaled, intravenous, or subcutaneous) have been the cornerstone of medical treatment. Atrial septostomy, heart and lung transplant, balloon pulmonary angioplasty, and pulmonary thromboendarterectomy are existing therapeutic options currently available. There has been a continuous effort to introduce newer therapies to improve life expectancy and modify disease. Newer therapies have shown promising results but require future data to guarantee long-term safety and efficacy. We aim to discuss a few of these critical updates in the constantly evolving field of PAH.

Substantial progress has been made in the management of pulmonary arterial hypertension (PAH) in the past 25 years, but the disease remains life-limiting. Established therapies for PAH are mostly limited to symptomatic relief by correcting the imbalance of vasoactive factors. The tyrosine kinase inhibitor imatinib, the first predominantly non-vasodilatory drug to be tested in patients with PAH, improved exercise capacity and pulmonary haemodynamics compared with placebo but at the expense of adverse events such as subdural haematoma. Given that administration by inhalation might reduce the risk of systemic adverse effects, inhaled formulations of tyrosine kinase inhibitors are currently in clinical development. Other novel therapeutic approaches for PAH include suppression of activin receptor type IIA signalling with sotatercept, which has shown substantial efficacy in clinical trials and was approved for use in the USA in 2024, but the long-term safety of the drug remains unclear. Future advances in the management of PAH will focus on right ventricular function and involve deep phenotyping and the development of a personalized medicine approach. In this Review, we summarize the mechanisms underlying PAH, provide an overview of available PAH therapies and their limitations, describe the development of newer, predominantly non-vasodilatory drugs that are currently being tested in phase II or III clinical trials, and discuss future directions for PAH research.

There are several pharmacologic agents that have been touted as guideline-directed medical therapy for heart failure with preserved ejection fraction (HFpEF). However, it is important to recognize that older adults with HFpEF also contend with an increased risk for adverse effects from medications due to age-related changes in pharmacokinetics and pharmacodynamics of medications, as well as the concurrence of geriatric conditions such as polypharmacy and frailty. With this review, we discuss the underlying evidence for the benefits of various treatments in HFpEF and incorporate key considerations for older adults, a subpopulation that may be at higher risk for adverse drug events. Key considerations for older adults include: the use of loop diuretics, mineralocorticoid receptor antagonists (MRAs), and sodium glucose co-transporter-2 (SGLT2) inhibitors for most; angiotensin receptor blockers/ angiotensin receptor-neprilysin inhibitors (ARB/ARNIs) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) as add-on therapies for some, though risk of geriatric conditions such as falls, malnutrition, and/or sarcopenia must be considered; and beta blockers for a smaller subset of patients (with consideration of deprescribing for some, though data are lacking on this approach). Naturally, when making clinical decisions for older adults with cardiovascular disease, it is critical to consider the complexity of their conditions, including cognitive and physical function and social and environmental factors, and ensure alignment of care plans with the patient's health goals and priorities.

Age is a major risk factor for heart failure, but one that has been historically viewed as non-modifiable. Emerging evidence suggests that the biology of aging is malleable, and can potentially be intervened upon to treat age-associated chronic diseases, such as heart failure. While aging biology represents a new frontier for therapeutic target discovery in heart failure, the challenges of translating Geroscience research to the clinic are multifold. In this review, we propose a strategy that prioritizes initial target discovery in human biology. We review the rationale for starting with human omics, which has generated important insights into the shared (patho)biology of human aging and heart failure. We then discuss how this knowledge can be leveraged to identify the mechanisms of aging biology most relevant to heart failure. Lastly, we provide examples of how this human-first Geroscience approach, when paired with rigorous functional assessments in preclinical models, is leading to early-stage clinical development of gerotherapeutic approaches for heart failure.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by proliferative remodeling and obliterative narrowing of the pulmonary vasculature. While outcomes have improved with existing treatments targeting 3 main pathways, there remains a critical need for novel therapies that address different and novel mechanisms of PAH. Sotatercept, recently Food and Drug Administration (FDA) approved, is a groundbreaking fusion protein that binds to activin and growth differentiation factors, rebalancing antiproliferative and pro-proliferative signals to reverse remodeling in both the pulmonary vasculature and the right ventricle. This review highlights current evidence exploring the safety and efficacy of sotatercept in the 2 landmark trials, phase 2 Pulmonary Arterial Hypertension and Sotatercept Trial and Research and phase 3 Sotatercept Treatment in Expansion of Long-term Learning and Assessment in PAH trial, which were instrumental in securing FDA approval for adult PAH patients with WHO functional class II or III symptoms already receiving background pulmonary hypertension therapy. Overall, sotatercept represents a landmark advancement in PAH treatment, offering hope for patients and the potential to delay or avoid lung transplantation. Importantly, this marks the beginning of an era of targeted therapies aimed at reverse remodeling in PAH while improving outcomes.

Pulmonary vascular disease is not a single condition; rather it can accompany a variety of pathologies that impact the pulmonary vasculature. Applying precision medicine strategies to better phenotype, diagnose, monitor, and treat pulmonary vascular disease is increasingly possible with the growing accessibility of powerful clinical and research tools. Nevertheless, challenges exist in implementing these tools to optimal effect. The 2023 Grover Conference Series reviewed the research landscape to summarize the current state of the art and provide a better understanding of the application of precision medicine to managing pulmonary vascular disease. In particular, the following aspects were discussed: (1) Clinical phenotypes, (2) genetics, (3) epigenetics, (4) biomarker discovery, (5) application of precision biology to clinical trials, (6) the right ventricle (RV), and (7) integrating precision medicine to clinical care. The present review summarizes the content of these discussions and the prospects for the future.

This review focuses on the advancements in the treatment of pulmonary hypertension (PH), especially after the Food and Drug Administration (FDA) approval of sotatercept and the advances in treatment recommendations after seven World Symposia on PH. PH, a complex and progressive condition defined hemodynamically by a mean pulmonary artery pressure >20 mmHg, encompasses multiple PH groups, each with distinct pathophysiological characteristics and treatment implications. Diagnosing PH can be challenging because symptoms like shortness of breath, fatigue, and chest pain are nonspecific. Contemporary treatment of pulmonary arterial hypertension aims to improve outcomes, symptoms, and overall quality of life, with a primary focus on preventing and treating right ventricular failure. Comprehensive risk stratification remains crucial, aiding in personalized therapy adjustments that improve patients' outcomes. This review also touches upon the limited treatment options for other PH groups, like PH associated with left heart disease, parenchymal lung diseases, and chronic thromboembolic PH, underscoring the need for expanded therapeutic options. Despite advances, challenges remain: diagnostic delays, misdiagnosis, absence of head-to-head clinical trials, and the timing of introducing newer treatments such as sotatercept are discussed, emphasizing an integrated approach that transcends vasodilation to target underlying disease mechanisms. Future directions envision a comprehensive risk stratification incorporating right ventricular function and a mechanism-based treatment paradigm, encouraging a tailored therapeutic approach in PH management.

Pulmonary arterial hypertension (PAH) is a severe disorder of the pulmonary vasculature leading to right ventricular failure. This pulmonary vascular remodelling leads to increased pulmonary vascular resistance and high pulmonary arterial pressures. Despite the development of new therapies, many patients continue to experience significant morbidity and mortality. This review offers a comprehensive overview of the current understanding of PAH pathophysiology, with a focus on key mechanisms that contribute to pulmonary endothelial cell dysfunction and the pathological accumulation of pulmonary artery smooth muscle cells, mesenchymal cells and inflammatory cells in the walls of remodelled small pulmonary vessels, three processes central to the progression of PAH. In particular, it highlights recent developments in targeting the activin signalling pathway, a novel therapeutic approach that shows promise in modulating these pathological processes. The review also addresses the ongoing challenges in translating preclinical findings into effective clinical treatments, emphasising the importance of integrating human data with preclinical models and adopting innovative strategies to bridge the gap between research and clinical practice.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive obliteration of pulmonary arteries. Dysregulated bone morphogenetic protein (BMP) signaling pathway contributes to the development of PAH, and pulmonary vasodilators including endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostaglandins and soluble guanylate cyclase stimulators, dramatically improve the long-term prognosis. However, there still exist refractory patients who require continuous catecholamine support or lung transplantation, and the development of new treatment strategies targeting molecular mechanisms of PAH is highly anticipated. Sotatercept, a first-in-class activin signaling inhibitor, has recently been approved for the treatment of PAH, and it targets and restores an imbalance in activin-growth differentiation factor and BMP pathway signaling. In addition, treatment strategies targeting peroxisome proliferator-activated receptor-γ signaling, inflammatory and immune systems, DNA damage response and cellular senescence, and growth factor receptors including vascular endothelial growth factor and platelet-derived growth factor receptors, are being devised. In this review, we briefly summarize the recent advances in basic research paving the way for the development of more effective treatments for PAH and their potential in clinical therapeutic applications.

Ventricular remodeling in right heart failure is a complex pathological process involving interactions between multiple mechanisms. Overactivation of the neuro-hormonal pathways, activation of the oxidative stress response, expression of cytokines, apoptosis of cardiomyocytes, and alterations of the extracellular matrix (ECM) are among the major mechanisms involved in the development of ventricular remodeling in right heart failure. These mechanisms are involved in ventricular remodeling, such as myocardial hypertrophy and fibrosis, leading to the deterioration of myocardial systolic and diastolic function. A deeper understanding of these mechanisms can help develop more effective therapeutic strategies in patients with right heart failure (RHF) to improve patient survival and quality of life. Despite the importance of ventricular remodeling in RHF, there are a limited number of studies in this field. This article explores in-depth historical and current information about the specific mechanisms in ventricular remodeling in RHF, providing a theoretical rationale for recognizing its importance in health and disease.

Sotatercept (brand name WINREVAIR, developed by Merck) is an activin receptor type IIA-Fc (ActRIIA-Fc), working by sequestering free activins. Sotatercept restores the balance between the activin proliferative pathway and the bone morphogenic protein (BMP) antiproliferative pathway in the pulmonary arterial cirulation. Sotatercept recently received approval in the USA and in Europe for the treatment of adults with pulmonary arterial hypertension (PAH) Group 1, on top of background PAH therapy to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events. Nevertheless, several studies are ongoing to investigate the potential adverse reactions of the drug especially at the haematological level. We provide an overview of the clinical and preclinical evidence of the targeting the activing pathway through sotatercept on the treatment of PAH. We also discuss what other possibilities there are for the application of sotatercept in the setting of pulmonary hypertension other than PAH Group 1.

Pulmonary arterial hypertension (PAH), one subtype of pulmonary hypertension (PH), is a life-threatening condition characterized by pulmonary arterial remodeling, elevated pulmonary vascular resistance, and blood pressure in the pulmonary arteries, leading to right heart failure and increased mortality. The disease is marked by endothelial dysfunction, vasoconstriction, and vascular remodeling. The role of Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitors, a class of medications originally developed for diabetes management, is increasingly being explored in the context of cardiovascular diseases, including PAH, due to their potential to modulate these pathophysiological processes. In this review, we systematically examine the burgeoning evidence from both basic and clinical studies that describe the effects of SGLT2 inhibitors on cardiovascular health, with a special emphasis on PAH. By delving into the complex interactions between these drugs and the potential pathobiology that underpins PH, this study seeks to uncover the mechanistic underpinnings that could justify the use of SGLT2 inhibitors as a novel therapeutic approach for PAH. We collate findings that illustrate how SGLT2 inhibitors may influence the normal function of pulmonary arteries, possibly alleviating the pathological hallmarks of PAH such as inflammation, oxidative stress, aberrant cellular proliferation, and so on. Our review thereby outlines a potential paradigm shift in PAH management, suggesting that these inhibitors could play a crucial role in modulating the disease's progression by targeting the potential dysfunctions that drive it. This comprehensive synthesis of existing research underscores the imperative need for further clinical trials to validate the efficacy of SGLT2 inhibitors in PAH and to integrate them into the therapeutic agents used against this challenging disease.

The dysregulation of N6-methyladenosine (m6A) RNA modification is widely recognized for its crucial roles in various diseases, including pulmonary hypertension (PH). Prior studies have highlighted the significant role of methyltransferase-like 3 (METTL3) in the pathogenesis of PH. Nevertheless, the potential and underlying mechanisms of METTL3 and its inhibitors as targets for PH treatment require further elucidation. In this study, increased levels of METTL3 were observed in various rodent models of PH. In vitro studies revealed that METTL3 silencing or treatment with STM2457, a specific METTL3 inhibitor, attenuated the proliferation and migration of pulmonary artery smooth muscle cells stimulated by platelet-derived growth factor-BB or hypoxia. Moreover, in vivo experiments using adeno-associated virus 9-mediated METTL3 silencing or STM2457 inhibition demonstrated improvement in SU5416/hypoxia-induced PH in mice. Additionally, m6A RNA immunoprecipitation analysis identified recombination signal binding protein for immunoglobulin kappa J region (RBPJ) regulated by METTL3 in rodent models of PH. Loss-of-function studies showed that silencing RBPJ could attenuate the changes in the proliferation and migration of pulmonary artery smooth muscle cells induced by platelet-derived growth factor-BB or hypoxia. Further studies indicated that METTL3 and YTH N6-methyladenosine RNA binding protein F1 (YTHDF1) regulated RBPJ mRNA expression in an m6A-dependent manner. These findings indicated that targeting METTL3 may be a promising therapeutic strategy for treating PH, and modulation of RBPJ could offer a potential intervention mechanism.

Identification and validation of potential biomarkers could facilitate the identification of pulmonary arterial hypertension (PAH) and thus aid to study their roles in the disease process.

We used the isobaric tag for relative and absolute quantitation approaches to compare the protein profiles between the serum of PAH patients and the controls. Bioinformatics analyses and enzyme-linked immunosorbent assay (ELISA) identification of PAH patients and the controls were performed to identify the potential biomarkers. The receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic performance of these potential biomarkers. Mendelian randomization (MR) analysis further clarified the relationship between the potential biomarkers and PAH. Additionally, the expression levels of the potential biomarkers were further validated in two PAH animal models (monocrotaline-PH and Sugen5416 plus hypoxia-PH) using ELISA and reverse transcription-quantitative PCR (RT-qPCR).

We identified significant changes in three proteins including heparanase (HPSE), gelsolin (GSN), and hepatocyte growth factor activator (HGFA) in PAH patients. The ROC analysis showed that the areas under the curve of HPSE, GSN, and HGFA in differentiating PAH patients from controls were 0.769, 0.777, and 0.964, respectively. HGFA was correlated with multiple parameters of right ventricular functions in PAH patients. Besides proteomic analysis, we also used MR method to demonstrate the causal link between genetically reduced HGFA levels and an increased risk of PAH. In subsequent validation study in PAH animal models, the mRNA expression levels of HGFA in the lung tissues were significantly lower in PAH rat models than in controls. In the rat models, serum levels of HGFA were lower compared to the control group and showed a negative correlation with right ventricular systolic pressure.

The study demonstrated that HGFA might be a promising biomarker for noninvasive detection of PAH.

Smad5 (small mothers against decapentaplegic 5) protein is a receptor-regulated member of the Smad family proteins, mainly participating in the bone morphogenetic protein (BMP) signaling pathway in its phosphorylated form. This article will provide a detailed review of Smad5, focusing on its gene characteristics, protein structure, and subcellular localization properties. We will also explore the related signaling pathways and the mechanisms of Smad5 in respiratory diseases, including chronic obstructive pulmonary disease (COPD), bronchial asthma, pulmonary arterial hypertension(PAH), lung cancer, and idiopathic pulmonary fibrosis (IPF). Additionally, the review will cover aspects such as proliferation, differentiation, apoptosis, anti-fibrosis, and mitochondrial function metabolism. In addition, the review will cover aspects of proliferation, differentiation, apoptosis, anti-fibrosis and functional mitochondrial metabolism related to the above topics. Numerous studies suggest that Smad5 may play a unique and important role in the pathogenesis of respiratory system diseases. However, in previous research, Smad5 was mainly used to broadly determine the activation of the BMP signaling pathway, and its own function has not been given much attention. It is worth noting that Smad5 has distinct nuclear-cytoplasmic distribution characteristics different from Smad1 and Smad8. It can undergo significant nuclear-cytoplasmic shuttling when intracellular pH (pHi) changes, playing important roles in both the classical BMP signaling pathway and non-BMP signaling pathways. Given that Smad5 can move intracellularly in response to changes in physicochemical properties, its cellular localization may play a crucial role in the development of respiratory diseases. This article will explore the possibility that its distribution characteristics may be an important factor that is easily overlooked and not adequately considered in disease research.

Low back pain (LBP) is a significant global health issue, contributing to disability and socioeconomic burdens worldwide. The degeneration of the human intervertebral disc (IVD) is a critical factor in the pathogenesis of LBP. Recent studies have emphasized the significance of a specific set of genes and extracellular matrix (ECM) in IVD health. In particular, Noggin has emerged as a critical gene due to its high expression levels in healthy nucleus pulposus cells (NPCs) observed in our previous research. In this study, it was hypothesized that decreased Noggin expression in NPCs is associated with IVD degeneration and contributes to LBP development. A lentivirus-mediated RNAi was applied to knock down Noggin expression in primary NPCs from six human donors. The NPCs after transduction were evaluated through cell viability analysis, XTT assay, and cell apoptosis analyses. After two weeks, a colony formation assay was used to examine the anchor-independent growth ability of transduced cells. At the transcript level, anabolic and catabolic markers were quantified using RT-qPCR. The results demonstrated that lentivirus-mediated downregulation of Noggin significantly inhibited cell proliferation, reduced cell viability, and suppressed colony formation, while inducing apoptosis in human NPCs in vitro. Notably, it disrupted cellular anabolic processes and promoted catabolic activity in human NPCs post-transduction. Our findings indicated that the degeneration of human IVD is possibly related to decreased Noggin expression in NPCs. This research provides valuable insights into the role of Noggin in IVD homeostasis and its implications in LBP treatment.

Growth differentiation factor 11 (GDF11) belongs to the transforming growth factor beta superfamily and participates in various pathophysiological processes. Initially, GDF11 was suggested to act as a rejuvenator by improving age-related phenotypes of the heart, brain, and skeletal muscle in aged mice. Recent studies demonstrate that GDF11 also serves as an adverse risk factor for human frailty and diseases. However, the role of GDF11 in pulmonary fibrosis (PF) remains unclear. This study explored the role and signaling mechanisms of GDF11 in PF. GDF11 expression was markedly up-regulated in fibrotic lung tissues of both humans and mice. Intratracheal administration of commercial recombinant GDF11 caused lung injury, inflammation, and fibrogenesis in mice. Furthermore, adenovirus-mediated secretory expression of mature GDF11 was exacerbated, whereas full-length GDF11 or the GDF11 propeptide (GDF111-298) alleviated bleomycin-induced PF in mice. In in vitro experiments, GDF11 suppressed the growth of alveolar and bronchial epithelial cells (A549 and BEAS-2B) and human pulmonary microvascular endothelial cells, promoted fibroblast activation, and induced epithelial/endothelial-mesenchymal transition. These effects corresponded to the phosphorylation of Smad2/3, and blocking activin A receptor type II-like kinase, 53kDa (ALK5)-Smad2/3 signaling abolished the in vivo and in vitro effects of GDF11. In conclusion, these findings provide evidence that GDF11 acts as a potent injurious, proinflammatory, and profibrotic factor in the lungs via the ALK5-Smad2/3 pathway.

The exploration of novel therapeutic avenues for skeletal muscle atrophy is imperative due to its significant health impact. Recent studies have spotlighted growth differentiation factor 11 (GDF11), a TGFβ superfamily member, for its rejuvenating role in reversing age-related tissue dysfunction. This review synthesizes current findings on GDF11, elucidating its distinct biological functions and the ongoing debates regarding its efficacy in muscle homeostasis. By addressing discrepancies in current research outcomes and its ambiguous role due to its homological identity to myostatin, a negative regulator of muscle mass, this review aims to clarify the role of GDF11 in muscle homeostasis and its potential as a therapeutic target for muscle atrophy. Through a thorough examination of GDF11's mechanisms and effects, this review provides insights that could pave the way for innovative treatments for muscle atrophy, emphasizing the need and strategies to boost endogenous GDF11 levels for therapeutic potential.

Pulmonary arterial hypertension (PAH) is a rare and progressive disease that continues to remain highly morbid despite multiple advances in medical therapies. There remains a persistent and desperate need to identify novel methods of treating and, ideally, reversing the pathologic vasculopathy that results in PAH development and progression. Sotatercept is a first-in-class fusion protein that is believed to primarily inhibit activin signaling resulting in decreased cell proliferation and differentiation, though the exact mechanism remains uncertain. Here, we review the currently available PAH therapies, data highlighting the importance of transforming growth factor-β (TGF-β) superfamily signaling in the development of PAH, and the published and on-going clinical trials evaluating sotatercept in the treatment of PAH. We will also discuss preclinical data supporting the potential use of the fusion protein KER-012 in the inhibition of aberrant TGF-β superfamily signaling to ameliorate the obstructive vasculopathy of PAH.