Yuhu He

BACKGROUND: Maladaptive vascular remodeling is a hallmark of pulmonary hypertension (PH), and therapeutic strategies directly targeting the pathological activity of smooth muscle cells remain limited. Metabolic and epigenetic dysregulation are established drivers of PH, and lysine lactylation has emerged as a novel posttranslational modification implicated in diverse diseases; however, its direct contribution to PH progression remains undefined. METHODS: Integrated lactylomic and proteomic profiling was performed in hypoxic human pulmonary arterial smooth muscle cells. The functional role of ALDOA (aldolase A) lactylation at lysine 42 (K42) was assessed using site-specific mutant virus and smooth muscle cell-specific inducible ALDOA knockout mice in 2 established PH models: SU5416+hypoxia in mice and monocrotaline in rats. RESULTS: We identified ALDOA as a prominent lactylation target in hypoxic pulmonary arterial smooth muscle cells, with K42 lactylation consistently elevated in primary pulmonary arterial smooth muscle cells derived from PH rodent models and human PH tissues. Mechanistically, AARS1 (alanyl-tRNA synthetase 1)-mediated ALDOA K42 lactylation enhanced its binding to γ-actin, independent of glycolytic activity. This lactylation-enhanced interaction promoted F-actin polymerization and activated YAP (Yes-associated protein) signaling via LATS1 (large tumor suppressor kinase 1) inhibition, thereby driving pulmonary arterial smooth muscle cell proliferation and phenotypic switching. Moreover, YAP/TEAD4 (TEA domain transcription factor 4)-mediated transcriptional upregulation of AARS1 established a positive feedback loop reinforcing ALDOA K42 lactylation under hypoxia. In vivo, ALDOA inducible knockout or reconstitution with the lactylation-deficient K42R (lysine 42 mutant to arginine) mutant attenuated experimental PH progression, with suppressed F-actin/YAP activation and reduced vascular remodeling. Furthermore, competitive inhibition of lactylation through β‑alanine reduced ALDOA K42 lactylation and ameliorated vascular remodeling in ALDOA-overexpressing rodent PH models. Translationally, pharmacological disruption of the ALDOA/γ-actin interaction by raltegravir suppressed cytoskeletal reorganization and YAP signaling, mitigating PH progression in both mouse and rat models. CONCLUSIONS: AARS1-mediated ALDOA K42 lactylation drives pulmonary vascular remodeling through a mechanism independent of ALDOA’s catalytic activity, promoting F-actin polymerization and YAP activation. Precision targeting of this modification selectively inhibits pathological signaling while preserving metabolic homeostasis, highlighting a translational potential for precision intervention in PH.

Aims: The landscape of insulin delivery is evolving, transitioning from hybrid automated insulin delivery (AID) to more sophisticated fully AID systems. We aimed to compare the efficacy of fully AID systems with any insulin delivery method in type 1 diabetes (T1D). Materials and Methods: Following registration in PROSPERO, CRD42024528669, PubMed, Embase, Cochrane Library and Web of Science were searched up to 26 February 2025 for randomised clinical trials comparing fully AID systems to any insulin delivery method in T1D. The control treatments included conventional insulin therapy (multiple daily injections, continuous subcutaneous insulin infusion and sensor‐augmented pumps) and hybrid AID systems. The primary outcome was the mean difference (MD) in the percentage of time blood glucose concentration remained in the target range (3.9–10.0 mmol/L or 4.0–10.0 mmol/L), assessed by random‐effects models. Results: We identified 1308 reports; after exclusions, 16 trials (669 patients) were included. Time in range (TIR) was higher using fully AID systems than control treatments (MD 9.99% [95% confidence interval, 3.75% to 16.22%], p = 0.002). This improvement was accompanied by increased diabetes treatment satisfaction (MD 3.70 points [95% confidence interval, 0.22 points to 7.18 points], p = 0.04). Fully AID systems exhibited a favourable effect on TIR when compared with conventional insulin therapy, while exhibiting an opposite effect when compared with hybrid AID (17.44% vs. −3.05%, p < 0.001). Younger patients with T1D, as well as patients with a shorter diabetes duration, exhibited more significant glycaemic improvements with fully AID systems therapy. Conclusions: Fully AID systems improved glycaemic control and diabetes treatment satisfaction compared with other non‐AID methods in patients with T1D, especially for younger patients. However, to achieve or exceed the desired benefits of hybrid AID, algorithm upgradation, along with the synergistic integration of multiple hormones, will be crucial for next‐generation fully AID systems.

Pulmonary arterial hypertension (PAH) is a complex and progressive disease characterized by elevated pulmonary artery pressure and vascular remodeling. Recent studies have underscored the pivotal role of metabolic dysregulation and epigenetic modifications in the pathogenesis of PAH. Lactate, a byproduct of glycolysis, is now recognized as a key molecule that links cellular metabolism with activity regulation. Recent findings indicate that, in addition to altered glycolytic activity and dysregulated. Lactate homeostasis and lactylation—a novel epigenetic modification—also play a significant role in the development of PAH. This review synthesizes current knowledge regarding the relationship between altered glycolytic activity and PAH, with a particular focus on the cumulative effects of lactate in pulmonary vascular cells. Furthermore, lactylation, an emerging epigenetic modification, is discussed in the context of PAH. By elucidating the complex interplay between lactate metabolism and lactylation in PAH, this review aims to provide insights into potential therapeutic targets. Understanding these metabolic pathways may lead to innovative strategies for managing PAH and improving patient outcomes. Future research should focus on the underlying mechanisms through which lactylation influences the pathophysiology of PAH, thereby aiding in the development of targeted interventions.

Background: Individuals are exposed to various volatile organic compounds (VOCs) in their surroundings. VOCs were associated with some cardiovascular and metabolic diseases, but the effects on blood pressure (BP) have not yet been clarified. This study aimed to ascertain the relationship between the urine levels of VOCs and the prevalence of hypertension (HTN) in the general population. Methods: This analysis utilized data from 4156 participants aged from 20 to 79 years in 2013–2018 National Health and Nutrition Examination Survey (NHANES). Exposure to VOCs was assessed through measurements of urinary VOC metabolites, with 16 VOCs selected for analysis. The relationships between VOCs and the risk of HTN in patients were examined through the weighted logistic regression and the weighted linear regression models. Generalized additive models were employed to analyze potential nonlinear associations between VOCs and the risk of HTN. Additionally, subgroup analyses and intergroup interaction tests were conducted. Results: A total of 4156 participants with 16 VOCs were finally included for analysis. Multivariable logistic regression showed that ln-transformed urine levels of N-acetyl-S-(2-cyanoethyl)-L-cysteine (CYMA) [odds ratio (OR) 1.54; 95% confidence interval (CI) 1.18–2.02], N-acetyl-S-(3-hydroxypropyl)-L-cysteine (3HPMA; OR 1.33; 95% CI 1.03–1.74), N-acetyl-S-(4-hydroxy-2-butenyl)-L-cysteine (MHBMA3; OR 1.68; 95% CI 1.29–2.20), and N-acetyl-S-(1-phenyl-2-hydroxyethyl)-L-cysteine + N-acetyl-S-(2-phenyl-2-hydroxyethyl)-L-cysteine (PHEMA; OR 1.55; 95% CI 1.19–2.00) were significantly associated with an increased risk of HTN in US general population. A nonlinear relationship and a threshold effect were only observed between ln (N-acetyl-S-(2-hydroxypropyl)-L-cysteine or 2HPMA) and HTN. There was a significantly positive correlation between ln(2HPMA) and HTN when ln(2HPMA) at least 5.29. Sub-analysis revealed that there was a more pronounced association in the elderly group (age ≥60 years), the overweight group (BMI ≥25), and the alcohol consumption group. Conclusion: Our work presents novel epidemiological evidence supporting the establishment of the relationship between environmental pollutants and HTN, highlighting hitherto ignored positive correlations between nonoccupational VOC exposure and the entire population's risk of HTN.

BACKGROUND: Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling, which involves aberrant proliferation and apoptosis resistance of the pulmonary arterial smooth muscle cells (PASMCs), resembling the hallmark characteristics of cancer. In cancer, the HMGB2 (high-mobility group box 2) protein promotes the pro-proliferative/antiapoptotic phenotype. However, the function of HMGB2 in PH remains uninvestigated. METHODS: Smooth muscle cell (SMC)–specific HMGB2 knockout or HMGB2-OE (HMGB2 overexpression) mice and HMGB2 silenced rats were used to establish hypoxia+Su5416 (HySu)-induced PH mouse and monocrotaline-induced PH rat models, respectively. The effects of HMGB2 and its underlying mechanisms were subsequently elucidated using RNA-sequencing and cellular and molecular biology analyses. Serum HMGB2 levels were measured in the controls and patients with pulmonary arterial (PA) hypertension. RESULTS: HMGB2 expression was markedly increased in the PAs of patients with PA hypertension and PH rodent models and was predominantly localized in PASMCs. SMC-specific HMGB2 deficiency or silencing attenuated PH development and pulmonary vascular remodeling in hypoxia+Su5416-induced mice and monocrotaline-treated rats. SMC-specific HMGB2 overexpression aggravated hypoxia+Su5416-induced PH. HMGB2 knockdown inhibited PASMC proliferation in vitro in response to PDGF-BB (platelet-derived growth factor-BB). In contrast, HMGB2 protein stimulation caused the hyperproliferation of PASMCs. In addition, HMGB2 promoted PASMC proliferation and the development of PH by RAGE (receptor for advanced glycation end products)/FAK (focal adhesion kinase)-mediated Hippo/YAP (yes-associated protein) signaling suppression. Serum HMGB2 levels were significantly increased in patients with PA hypertension, and they correlated with disease severity, predicting worse survival. CONCLUSIONS: Our findings indicate that targeting HMGB2 might be a novel therapeutic strategy for treating PH. Serum HMGB2 levels could serve as a novel biomarker for diagnosing PA hypertension and determining its prognosis.

Aims Inflammation is central to the pathogenesis of metabolic syndrome (MetS). Leukocyte cell-derived chemotaxin 2 (LECT2) is constitutively secreted in response to inflammatory stimuli and oxidative stress contributing to tissue or systemic inflammation. We explored the relationship between LECT2 levels and MetS severity in humans and mice. Methods Serum LECT2 levels were measured in 210 participants with MetS and 114 without MetS (non-MetS). LECT2 expression in the liver and adipose tissue was also examined in mice fed a high-fat diet (HFD) and genetically obese (ob/ob) mice. Results Serum LECT2 levels were significantly higher in MetS participants than in non-MetS participants (7.47[3.36–17.14] vs. 3.74[2.61–5.82], P < 0.001). Particularly, serum LECT2 levels were significantly elevated in participants with hypertension, central obesity, diabetes mellitus (DM), hyperglycaemia, elevated triglyceride (TG) levels, and reduced high-density lipoprotein cholesterol (HDL-C) levels compared to those in participants without these conditions. Pearson’s correlation analysis showed that serum LECT2 levels were positively associated with conventional risk factors in all patients. Moreover, LECT2 was positively associated with the number of MetS components (r = 0.355, P < 0.001), indicating that higher serum LECT2 levels reflected MetS severity. Multivariate regression analysis revealed that a one standard deviation increase in LECT2 was associated with an odds ratio of 1.52 (1.01–2.29, P = 0.044) for MetS prevalence after adjusting for age, sex, body mass index, waist circumference, smoking status, white blood cell count, fasting blood glucose, TG, total cholesterol, HDL-C, blood urea nitrogen, and alanine aminotransferase. Receiver operating characteristic curve analysis confirmed the strong predictive ability of serum LECT2 levels for MetS. The optimum serum LECT2 cut-off value was 9.05. The area under the curve was 0.73 (95% confidence interval 0.68–0.78, P < 0.001), with a sensitivity and specificity of 45.71% and 95.61%, respectively. Additionally, LECT2 expression levels were higher at baseline and dramatically enhanced in metabolic organs (e.g. the liver) and adipose tissue in HFD-induced obese mice and ob/ob mice. Conclusions Increased LECT2 levels were significantly and independently associated with the presence and severity of MetS, indicating that LECT2 could be used as a novel biomarker and clinical predictor of MetS. Graphical abstract

BACKGROUND: T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of hypertension remains unclear. METHODS: Peripheral blood samples were collected from patients with hypertension, and cluster of differentiation (CD)4+ T cells were sorted for gene expression and Western blotting analysis. TLGMNKO (T cell–specific LGMN-knockout) mice (Lgmn ^f/f /CD4 ^Cre ), regulatory T cell (Treg)–specific LGMN-knockout mice (Lgmn ^f/f /Foxp3 ^{YFP Cre} ), and RR-11a (LGMN inhibitor)–treated C57BL/6 mice were infused with Ang II (angiotensin II) or deoxycorticosterone acetate/salt to establish hypertensive animal models. Flow cytometry, 4-dimensional label-free proteomics, coimmunoprecipitation, Treg suppression, and in vivo Treg depletion or adoptive transfer were used to delineate the functional importance of T-cell LGMN in hypertension development. RESULTS: LGMN mRNA expression was increased in CD4+ T cells isolated from hypertensive patients and mice, was positively correlated with both systolic and diastolic blood pressure, and was negatively correlated with serum IL (interleukin)-10 levels. TLGMNKO mice exhibited reduced Ang II–induced or deoxycorticosterone acetate/salt–induced hypertension and target organ damage relative to wild-type (WT) mice. Genetic and pharmacological inhibition of LGMN blocked Ang II–induced or deoxycorticosterone acetate/salt–induced immunoinhibitory Treg reduction in the kidneys and blood. Anti-CD25 antibody depletion of Tregs abolished the protective effects against Ang II–induced hypertension in TLGMNKO mice, and LGMN deletion in Tregs prevented Ang II–induced hypertension in mice. Mechanistically, endogenous LGMN impaired Treg differentiation and function by directly interacting with and facilitating the degradation of TRAF6 (tumor necrosis factor receptor–associated factor 6) via chaperone-mediated autophagy, thereby inhibiting NF-κB (nuclear factor kappa B) activation. Adoptive transfer of LGMN-deficient Tregs reversed Ang II–induced hypertension, whereas depletion of TRAF6 in LGMN-deficient Tregs blocked the protective effects. CONCLUSIONS: LGMN deficiency in T cells prevents hypertension and its complications by promoting Treg differentiation and function. Specifically targeting LGMN in Tregs may be an innovative approach for hypertension treatment.

Background: Pulmonary arterial hypertension (PAH), Group 1 pulmonary hypertension (PH), is a type of pulmonary vascular disease characterized by abnormal contraction and remodeling of the pulmonary arterioles, manifested by pulmonary vascular resistance (PVR) and increased pulmonary arterial pressure, eventually leading to right heart failure or even death. The mechanisms involved in this process include inflammation, vascular matrix remodeling, endothelial cell apoptosis and proliferation, vasoconstriction, vascular smooth muscle cell proliferation and hypertrophy. In this study, we review the mechanisms of action of prostaglandins and their receptors in PAH. Main body: PAH-targeted therapies, such as endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, activators of soluble guanylate cyclase, prostacyclin, and prostacyclin analogs, improve PVR, mean pulmonary arterial pressure, and the six-minute walk distance, cardiac output and exercise capacity and are licensed for patients with PAH; however, they have not been shown to reduce mortality. Current treatments for PAH primarily focus on inhibiting excessive pulmonary vasoconstriction, however, vascular remodeling is recalcitrant to currently available therapies. Lung transplantation remains the definitive treatment for patients with PAH. Therefore, it is imperative to identify novel targets for improving pulmonary vascular remodeling in PAH. Studies have confirmed that prostaglandins and their receptors play important roles in the occurrence and development of PAH through vasoconstriction, vascular smooth muscle cell proliferation and migration, inflammation, and extracellular matrix remodeling. Conclusion: Prostacyclin and related drugs have been used in the clinical treatment of PAH. Other prostaglandins also have the potential to treat PAH. This review provides ideas for the treatment of PAH and the discovery of new drug targets.

Background: Information regarding the impact of cardiovascular disease (CVD) on disease progression among patients with mild coronavirus disease 2019 (COVID-19) is limited. Methods: This study evaluated the association of underlying CVD with disease progression in patients with mild COVID-19. The primary outcome was the need to be transferred to intensive care due to disease progression. The patients were divided with and without CVD as well as stable and intensive care groups. Results: Of 332 patients with mild COVID-19, median age was 51 years (IQR, 40-59 years), and 200 (61.2%) were female. Of 48 (14.5%) patients with CVD, 23 (47.9%) progressed to severe disease status and required intensive care. Compared with patients without CVD, patients with CVD were older, and more likely to have fatigue, chest tightness, and myalgia. The rate of requiring intensive care was significantly higher among patients with CVD than in patients without CVD (47.92% vs. 12.4%; P<0.001). In subgroup analysis, rate of requiring intensive care was also higher among patients with either hypertension or coronary heart disease than in patients without hypertension or coronary heart disease. The multivariable regression model showed CVD served as an independent risk factor for intensive care (Odd ratio [OR], 2.652 [95% CI, 1.019-6.899]) after adjustment for various cofounders. Conclusions: Patients with mild COVID-19 complicating CVD in are susceptible to develop severe disease status and requirement for intensive care. Key Points: Question: What is the impact of coexisting cardiovascular diseases (CVD) on disease progression in patients with mild COVID-19? Findings: Although most patients with mild COVID-19 were discharged alive from hospital, approximately 47.9% patients with coexisting CVD developed severe disease status and required intensive care. CVD is an independent risk factor of intensive care among patients with mild COVID-19. Meaning: Coexisting CVD is associated with unfavorable outcomes among patients with mild COVID-19. Special monitoring is required for these patients to improve their outcome.