To evaluate the efficacy and safety of sitokiren (SPH3127) tablet in patients with mild-to-moderate essential hypertension in comparison to valsartan capsule. This multicentre, randomised, double-blind, parallel Phase III trial was designed in 2 stages. In the 1st stage, eligible patients were randomised to receive 50 mg, 100 mg or 200 mg of SPH3127 tablet or 80 mg of valsartan capsule once daily (QD) for 12 consecutive weeks. In the 2nd stage, eligible patients were randomised to receive assigned dose of SPH3127 tablet based on the results from the 1st stage or valsartan 80 mg QD for 12 consecutive weeks. Primary outcome was the change from baseline in mean sitting diastolic blood pressure (msDBP) at Week 12. Safety outcome measures included any adverse events. Exploratory outcomes included plasma concentration of SPH3127, as well as the assessment of the correlation between SPH3127 exposure with the level of renin inhibition, clinical efficacy and occurrence of adverse events. The 1st stage enrolled 189 patients, of which 129 eligible patients were randomised. High plasma renin activity (PRA) inhibitory effect (83

This study introduces an innovative electrochemical method for detecting site-specific phosphorylation on tyrosine residues of vascular endothelial growth factor receptor 2 (VEGFR2), crucial for assessing the risk of preeclampsia-induced cerebral hemorrhage. By combining a VEGFR2-targeting peptide molecular probe with copper ion-mediated bis-tyrosine cross-linking, the method enables specific and sensitive detection of VEGFR2 phosphorylation in clinical samples. The process, validated by distinct electrochemical signals from phosphorylation at tyrosine residues 951 and 1175, correlates with VEGFR2's role in regulating endothelial cell proliferation and blood-brain barrier permeability. This approach simplifies the detection process, eliminating the need for complex biological preparations, and provides rapid, reliable molecular modification insights. The ability to quantitatively assess phosphorylation states in peripheral blood samples highlights its potential for bedside diagnostics, offering advancement in electrochemical biosensing for early detection and management of preeclampsia.

Background Glutathione S-transferase kappa 1 (Gstk1) is known to be involved in antioxidant defense and mitochondrial function, yet its role in sepsis-induced myocardial injury (SMI) remains largely unexplored. This study aims to investigate the potential protective role of Gstk1 in LPS-induced myocardial injury and to elucidate its underlying mechanisms. Methods and results Using both in vivo and in vitro models of lipopolysaccharide (LPS)-induced myocardial injury, we found that cardiac-specific overexpression of Gstk1, achieved via viral delivery in mice, significantly improved cardiac function and structural integrity, attenuated the inflammatory response (IL-1β, IL-6, TNF-α), and suppressed pyroptosis (NLRP3, GSDMD-N, cleaved caspase-1). These in vivo findings were consistent with results from in vitro experiments. Conversely, Gstk1 knockdown exacerbated these detrimental effects. Mechanistically, Gstk1 overexpression improved mitochondrial function by restoring membrane potential, reducing superoxide production, increasing ATP levels, and inhibiting mitochondrial DNA (mtDNA) release. Further investigation revealed that Gstk1 exerts its protective effects by suppressing the cGAS/STING pathway. Conclusion Gstk1 plays a critical protective role in LPS-induced SMI by attenuating mitochondrial dysfunction, inhibiting inflammatory responses and pyroptosis, and modulating the cGAS/STING signaling pathway. These findings suggest Gstk1 as a potential therapeutic target for sepsis-related cardiac injury.

BACKGROUND:Novel biodegradable patent foramen ovale (PFO) closure devices offer a promising therapeutic option. The efficacy and safety of the novel biodegradable devices compared with nitinol devices have not yet been investigated in a randomized clinical trial. METHODS:This multicenter, randomized, noninferiority trial examined whether the novel biodegradable PFO closure device achieves comparable closure success rates as traditional nitinol devices while demonstrating disappearance of the protruding parts of the device on echocardiography. A total of 190 patients with PFO were enrolled and randomly assigned to receive either the biodegradable device (n=96) or the nitinol device (n=94). The primary efficacy end point was PFO closure success rate at 6 months postprocedure as demonstrated by contrast echocardiography. We continued to evaluate device-related complications, device disappearance on echocardiography, and closure success rates over a 24-month follow-up period. RESULTS:Successful PFO closure was achieved in 87 patients (90.63%) in the biodegradable device group and 86 patients (91.49%) in the nitinol device control group. The lower limit of the 95% CI of absolute difference was -8.98%, greater than the predefined noninferiority margin of -10%, confirming that the biodegradable device was not inferior to the nitinol device in terms of closure success. One patient in the trial group required surgical device removal because of intraprocedural deformation. No deaths, embolism, thrombus on the device, or erosion were observed in either group throughout the entire study period. Transthoracic echocardiography revealed that the hyperechoic area corresponding to the biodegradable device began decreasing within the first year after implantation and disappeared on echocardiography by 24 months after implantation. CONCLUSIONS:The novel biodegradable PFO closure device, which disappears on echocardiography within 24 months after implantation, demonstrates noninferiority to the traditional nitinol device in both efficacy and safety.

BACKGROUND:Hypertension is a major cardiovascular risk factor with an incompletely understood cause. We aimed to unravel its proteomic landscape and investigate potential molecular mechanisms underlying its risk related to modifiable exposures. METHODS:Leveraging protein quantitative trait loci from 3 biobank-scale studies (deCODE, Fenland, and UKB-PPP [UK Biobank Pharma Proteomics Project]) based on distinct proteomic platforms (SomaScan or Olink), we performed proteome-wide Mendelian randomization to identify and cross-platform validate proteins causally associated with hypertension and blood pressure (BP). Bayesian colocalization was applied to detect shared causal variants underpinning the identified associations. A broad range of modifiable risk factors were systematically assessed for their causal associations with hypertension/BP, followed by mediation analyses exploring potential proteomic pathways linking risk factors to hypertension/BP. RESULTS:The discovery Mendelian randomization analyses (deCODE) identified 190 significant causal associations between 118 proteins and hypertension/BP, which were overall consistent in the cross-platform replication analyses (Fenland and UKB-PPP). Fifty-four protein-hypertension/BP pairs were further supported by genetic colocalization. Triangulation of evidence from Mendelian randomization and colocalization prioritized 28 proteins as key causal signatures. Among these, 10 proteins (particularly ALDH2 [mitochondrial aldehyde dehydrogenase] and ULK3 [serine/threonine-protein kinase]) were found to mediate the associations of 8 genetically predicted modifiable risk factors with hypertension/BP, with ALDH2 emerging as a central hub across multiple causal pathways. CONCLUSIONS:This study systematically characterized the causal proteomic landscape of hypertension and highlighted proteins implicated in its modifiable risk. These findings provide novel insights into the molecular cause of hypertension and identify promising candidates for further therapeutic investigation.

Immune dysregulation is closely implicated in hypertension pathogenesis, yet specific therapeutic targets are lacking. We integrated expression quantitative trait loci (eQTLs) for genes expressed in 14 immune cell subsets (OneK1K) with two-sample Mendelian randomization (MR) and colocalization to provide evidence for cell type-specific causal effects of eGenes (genes with eQTLs) on hypertension and related complications (FinnGen and UK Biobank). Single cell-level expression of causal eGenes was compared between individuals with and without hypertension. A tiered framework was built to prioritize crucial eGenes for therapeutic translation. The druggability of the prioritized eGenes was surveyed, with potential on-target side effects evaluated using phenome-wide MR. Immune cell-specific expression of 172 eGenes was causally associated with hypertension, with prioritization of 17 eGenes performed by colocalization. eGenes in naïve and central memory CD4+ T cell (CD4 NC), effector memory CD8+ T cell (CD8 ET), and natural killer cell (NK) were most significantly associated with hypertension. Among these, FNBP4 and PRELID1 in multiple cell subsets moonlight as causal drivers of hypertensive heart disease. Higher expression levels of DDX5 in CD4 NC and CD8 NC, VIM in CD8 ET, and CTSW in NK were observed in hypertensive patients than normotensive controls. Most eGenes categorized as Tier 1 and 2 targets were druggable, and genetically mimicked therapeutics targeted at Tier 1 targets were predicted to generate limited on-target side effects. Our findings provided robust genetic insights into the immunological etiology of hypertension, opening up new avenues for the development of immune-mediated anti-hypertensive therapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder linked to metabolic syndrome, but its extrahepatic drivers and persistence mechanisms remain unclear. Transcriptomics was performed on adipose-derived stem cells (ADSCs) from distinct adipose depots in dynamic MASLD mouse models. A dietary reversal model was used to assess transcriptional retention. Candidate genes were identified via integrated DNA methylome and transcriptome analysis. Cyp26b1 function was tested by perirenal ADSCs-specific knockdown, and involved downstream mechanisms were investigated. Perirenal ADSCs exhibited an early dysregulated transcriptional signature in MASLD and retained high transcriptional retention after reversal. Multi-omics identified Cyp26b1 as a persistent, epigenetically regulated driver. Knockdown of Cyp26b1 in perirenal ADSCs attenuated MASLD progression, potentially by modulating the CCL3–CCR5 axis to alleviate hepatic steatosis and inflammation. This study reveals an ADSC-mediated perirenal adipose–liver axis and establishes pathological "memory" in ADSCs as a perpetuating factor in MASLD. Transcriptional retention in perirenal ADSCs and its key regulator Cyp26b1 represent potential theoretical targets for exploring the mechanism and intervention of cellular "memory" in MASLD.

The American College of Cardiology (ACC) and the American Heart Association (AHA) revised the diagnostic criteria for hypertension, recommending a lower threshold of 130/80 mmHg for nonpregnant adults. However, this lower threshold has not been adopted in the global obstetrics field. It remains unclear whether applying this new definition to pregnant women would have implications for maternal health and offspring development. The present study aimed to examine potential relationships between maternal borderline hypertension and neurodevelopmental outcomes in infants. This study is a secondary analysis conducted within the prospective Jiangsu Birth Cohort in China. A total of 3352 mothers with blood pressure (BP) records and 3641 of their children were included. Pregnant women were categorized as normotensive (systolic BP [SBP] < 130 mmHg and diastolic BP [DBP] < 80 mmHg), borderline hypertensive (SBP 130–139 mmHg and/or DBP 80–89 mmHg), or hypertensive (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg). Infant neurodevelopment was assessed using the Bayley-III screening test. General linear mixed-effects models and Poisson generalized linear mixed models were applied to evaluate potential associations between maternal borderline hypertension in different trimesters and offspring neurodevelopment, including continuous neurodevelopmental scores and the risk of non-typical development. Compared with offspring of normotensive mothers, those exposed to maternal borderline hypertension during the first trimester suggested a higher risk of non-typical development in receptive communication (risk ratio [RR], 1.25; 95

Thioredoxin reductase 2 (TrxR2), a radical-trapping antioxidant, plays a critical role in cardiac defense. However, the mechanisms underlying its benefits remain unclear. In this study, we aimed to investigate whether endothelial TrxR2 prevents cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Key genes in the thioredoxin family and those involved in ferroptosis were analyzed using bulk RNA-sequencing assay. Diabetic injury was induced in multiple transgenic mouse models, including endothelial cell-specific knockout mice for TrxR2, sterol carrier protein 2 (SCP2), and Tu translation elongation factor, mitochondrial (TUFM). The TrxR2 lactylation site was identified by mass spectrometry and verified by a custom-made lactylation antibody. Mitochondrial thioredoxin reductase (mitoTrxR) activity and lipid peroxyl radicals were detected using fluorescence staining. Endothelial TrxR2 deficiency significantly suppressed mitoTrxR activity, exacerbated cardiac microvascular dysfunction, and accelerated DCM progression. In contrast, TrxR2 overexpression and Kukoamine B (TrxR2 agonist) treatment inhibited mitochondria-associated ferroptosis by facilitating SCP2 degradation and blocking the mitochondrial translocation of acyl-CoA synthetase long-chain family member 4 (ACSL4) via mitophagy. Mechanistically, TrxR2 maintained TUFM expression by scavenging oxygen radicals, thereby facilitating the mitochondrial translocation of AMPK for mitophagy activation. TrxR2 undergoes lactylation at lysine 340. This process is mediated by mitochondrial alanyl-tRNA synthetase 2 (AARS2) and lactate accumulation in both human and mouse diabetic hearts. This modification and sodium lactate administration compensatorily enhanced mitoTrxR activity, promoted mitophagy, and conferred ferroptosis resistance in cardiac microcirculation in DCM. Our findings demonstrate that TrxR2 and its lactylation modification promote mitophagy, enhance ferroptosis resistance, and improve cardiac microvascular function in DCM. Thus, this study provides a promising therapeutic approach for the management of diabetic complications.

Background and purpose: Matching the anti-proliferative drug effect with endothelial healing after drug-eluting stent (DES) implantation may help reduce cardiac events, especially stent thrombosis. A previous PIONEER II optical coherence tomography (OCT) sub-study demonstrated significantly better 1-month strut coverage with the novel healing-targeted BuMA Supreme DES, which was designed with a drug elution period of 4 to 6 weeks after implantation, compared with the XIENCE everolimus eluting stent (EES). This clinical trial aimed to evaluate whether the early endothelial healing observed in previous OCT sub-study would translate into improved intermediate-term angiographic and short-term clinical outcomes. Methods: PIONEER II was a multicenter, prospective, tandem clinical trial conducted in China. It was part of a series of clinical investigations of the BuMA Supreme DES, together with PIONEER I in Europe and PIONEER III in the United States, Canada, Europe, and Japan. The efficacy and safety of the BuMA Supreme DES were evaluated in patients with de novo coronary artery lesions. Results: From December 2015 to March 2018, 459 patients were randomly assigned to the randomized controlled trial (RCT) arm and received either the BuMA Supreme DES (n = 226) or the BuMA biodegradable polymer sirolimus-eluting stent (BP-SES; n = 233). In addition, 819 patients were enrolled in the objective performance criteria (OPC) arm. In the RCT arm, the BuMA Supreme DES was non-inferior to the BuMA BP-SES with respect to 9-month in-stent late lumen loss (LLL), with values of 0.23 ± 0.37 mm and 0.27 ± 0.36 mm, respectively (difference: −0.046 mm, 95% confidence interval: −0.107 to 0.015; P < 0.001 for non-inferiority). Furthermore, the BuMA Supreme DES demonstrated significantly lower values for secondary angiographic endpoints, including in-segment LLL and in-stent/in-segment diameter stenosis, compared with the BuMA BP-SES. In the OPC arm analysis, which combined patients from the BuMA Supreme group of the RCT arm with patients enrolled in the single-arm cohort, the 1-year target lesion failure rate was 4.17%. Both primary endpoints met the pre-specified non-inferiority criteria. Conclusion: The BuMA Supreme DES was non-inferior to the BuMA BP-SES with respect to 9-month in-stent LLL and was associated with the expected target lesion failure rate and a low incidence of stent thrombosis at 1-year follow-up.

BACKGROUND:Transcatheter aortic valve replacement (TAVR) has advanced from an emerging technology to a standard therapeutic option for high-risk patients with symptomatic severe aortic stenosis. Procedural risk correlates strongly with aortic root anatomy. In elderly patients with bicuspid aortic valves, concomitant horizontal cardiac orientation and ascending aortic dilation confer markedly higher procedural risk. CASE SUMMARY:We report an elderly patient with a bicuspid aortic valve, severe horizontal aortic root angulation (88°), and ascending aortic dilation (approximately 60 mm). The presence of an ascending aortic aneurysm supported the indication for surgical intervention. Given the substantial technical complexity and perioperative risk of open-heart surgery, TAVR was selected as a safer alternative. DISCUSSION:This case demonstrates that TAVR remains feasible in elderly patients with complex anatomy unsuitable for surgery, despite increased procedural challenges and risk. TAKE-HOME MESSAGE:In elderly patients with severe aortic stenosis and anatomically complex aortic pathology, TAVR should be considered a clinically viable treatment strategy.

Background Cardiac fibrosis is a hallmark of ischemic heart failure and is driven by activated myofibroblasts. DNA damage and defective repair promote fibroblast activation, yet the upstream regulators that couple DNA damage responses to profibrotic remodeling remain unclear. Methods Single‐cell RNA sequencing data sets from human ischemic cardiomyopathy were analyzed to identify fibroblast‐enriched candidate genes. In vivo, Postn promoter‐driven adeno‐associated viruses were used to knock down or overexpress CRABP2 (cellular retinoic acid‐binding protein 2) in an isoproterenol‐induced mouse model, followed by assessment of ventricular function and fibrosis. In vitro, neonatal cardiac fibroblasts were subjected to CRABP2 gain or loss of function and TGF‐β (transforming growth factor‐β) stimulation. Mechanistic studies combined RNA sequencing, immunoprecipitation–mass spectrometry, structural modeling, γ‐H2AX staining, comet assays, and MRE11/MRE11‐RAD50‐NBS1 (MRN) perturbation. Results Single‐cell analyses identify CRABP2 as a fibroblast‐enriched gene upregulated in profibrotic fibroblast subsets in human ischemic hearts. In vivo, CRABP2 knockdown in Postn+ myofibroblasts preserves left ventricular function and attenuates interstitial fibrosis, whereas CRABP2 overexpression exacerbates dysfunction and fibrosis in isoproterenol‐treated mice. In vitro, CRABP2 promotes TGF‐β–induced fibroblast migration, proliferation, activation, and collagen production. Mechanistically, CRABP2 binds MRE11, suppresses MRN‐ATM‐CHK2 signaling, and enhances DNA damage accumulation. Inhibiting or silencing MRE11 abrogates the antifibrotic and cardioprotective effects of CRABP2. Conclusions CRABP2 drives profibrotic cardiac fibroblast activation by inhibiting MRE11/MRN‐mediated DNA repair. The CRABP2‐MRE11‐MRN axis represents a potential therapeutic target for limiting fibrotic remodeling in ischemic heart failure.

Adipose tissue serves as a crucial energy storage and metabolic organ in the human body. With the surging of elderly population in China comes significant challenges in preventing and managing age-associated diseases, while adipose tissue aging represents one of the pivotal initiating events for multi-organ senescence. To address these challenges, the Aging China Biomarkers Consortium (ABC) has established an expert consensus on biomarkers of adipose tissue aging by digesting literature and collecting insights from scientists and clinicians. This consensus provides a comprehensive evaluation of the key changes and characteristics, as well as biomarkers related to adipose tissue aging and proposes a systematic framework categorizing these biomarkers into functional, structural and humoral dimensions. Within each dimension, the ABC recommends clinically and empirically validated biomarkers and parameters for assessing both physiological and pathological changes in adipose tissue during aging, which aims to establish a foundation for future prediction, diagnosis, early warning and treatment for adipose tissue aging and its related diseases, with the ultimate goal of improving adipose tissue health and promoting healthy aging in elderly populations both in China and worldwide.

Background: Silent Brain Infarction (SBI) has been found to be linked to an increased risk of cognitive impairment and future symptomatic stroke. Atrial fibrillation is a significant risk factor for SBI. Even in low-risk atrial fibrillation patients, the incidence of SBI remains high. This study aims to investigate the risk factors for SBI in nonvalvular atrial fibrillation (NVAF) patients with a CHA2DS2-VASc score of 0 to 1. Methods: A total of 301 consecutive low-risk NVAF patients (male: CHA2DS2-VASc=0, female: CHA2DS2-VASc=1) were enrolled. According to brain Magnetic Resonance Imaging (MRI), patients were divided into SBI (n=90) and non-SBI (n=211) groups. Baseline characteristics, blood parameters, and echocardiography results were analyzed. Multivariate logistic regression was performed to identify independent predictors. Receiver Operating Characteristic (ROC) curve analysis was used to evaluate the diagnostic power of the relevant risk factors. Results: The study revealed that neutrophil count, monocyte count, Platelet-To-Lymphocyte Ratio (PLR), neutrophil-to-high density lipoprotein cholesterol ratio (NHR), and left atrial diameter (LAD) were significantly higher in the SBI group than non-SBI group (p <0.05). Multivariate logistic regression analysis identified PLR (OR, 1.004; 95%CI 1.001-1.007; p =0.026) and LAD (OR 1.092; 95%CI 1.054-1.130; p <0.001) as the independent risk factors associated with SBI. The ROC showed that the Area Under the Curve (AUC) of PLR is 0.589 (95%CI 0.515- 0.662; p =0.015) with an optimal cut-off point of 151 (sensitivity 43.3%, specificity 74.6%). The AUC of LAD is 0.676 (95%CI 0.606-0.746; p <0.001) with an optimal cut-off point of 39 mm (sensitivity 61.1%, specificity 72.0%). The AUC of PLR combined with LAD is 0.711 (95%CI 0.646-0.777; p <0.001) with a sensitivity of 63.3% and specificity of 73.5% for SBI. Conclusion: PLR and LAD can be independent risk factors for SBI in NVAF patients with low CHA2DS2-VASc scores. The combination of the two factors can enhance the predictive ability of SBI in these patients.

The extent of myocardial fibrosis is closely related to the prognosis of diabetic cardiomyopathy (DCM). Low-intensity pulsed ultrasound (LIPUS) has been reported to have multiple biological effects. However, the effect of LIPUS on diabetic heart fibrosis remains unclear. The present study aimed to investigate the effect of LIPUS on diabetic heart fibrosis and explore its underlying mechanisms. High glucose (HG) was applied to cultured neonatal rat cardiac fibroblasts (NRCFs) to mimic the in vivo hyperglycemia microenvironment. LIPUS (19.30 mW/cm2 to 77.20 mW/cm2) dose-dependently inhibited HG-induced fibrotic response in NRCFs. Also, LIPUS downregulated NADPH oxidase 4 (NOX4)-associated oxidative stress and nod-like receptor protein-3 (NLRP3) inflammasome activation in NRCFs. In vivo, diabetes in mice was induced with streptozotocin (STZ). Mice in the LIPUS group and STZ + LIPUS group were treated with LIPUS (77.20 mW/cm2) twice a week for 12 weeks and then euthanized at 12 weeks or 24 weeks post-diabetes. Treatment with LIPUS significantly ameliorated the progression of cardiac fibrosis (Masson staining 6.5 ± 2.3% vs. 2.8 ± 1.5%, P < 0.001) and dysfunction (E/A ratio 1.35 ± 0.14 vs. 1.59 ± 0.11, P < 0.05), as well as NOX4-associated oxidative stress (relative expression fold of NOX4 1.43 ± 0.12 vs. 1.07 ± 0.10, P < 0.01; relative DHE fluorescence 1.51 ± 0.13 vs. 1.28 ± 0.06, P < 0.05) and NLRP3 inflammasome activation (relative expression fold of NLRP3 1.57 ± 0.12 vs. 1.05 ± 0.16, P < 0.01), at 12 weeks post-diabetes. At 24 weeks post-diabetes, the heart function in diabetic mice treated with LIPUS was still significantly better than untreated diabetic mice (E/A ratio 1.08 ± 0.12 vs. 1.49 ± 0.14, P < 0.001). Further exploration revealed that LIPUS significantly attenuated the upregulated angiotensin-converting enzyme (ACE) and angiotensin II (AngII), in both HG-induced NRCFs and diabetic hearts (relative expression of ACE in myocardium 3.77 ± 0.55 vs. 1.07 ± 0.13, P < 0.001; AngII in myocardium 115.5 ± 21.77 ng/ml vs. 84.28 ± 9.03 ng/ml, P < 0.01). Captopril, an ACE inhibitor, inhibited NOX4-associated oxidative stress and NLRP3 inflammasome activation in both HG-induced NRCFs and diabetic hearts. Our results indicate that non-invasive local LIPUS therapy attenuated heart fibrosis and dysfunction in diabetic mice and the effect could be largely preserved at least 12 weeks after suspending LIPUS stimulation. LIPUS ameliorated diabetic heart fibrosis by inhibiting ACE-mediated NOX4-associated oxidative stress and NLRP3 inflammasome activation in cardiac fibroblasts. Our study may provide a novel therapeutic approach to hamper the progression of diabetic heart fibrosis.

BACKGROUND:Cardiac fibrosis is a major determinant of adverse clinical outcomes of many heart diseases; currently, therapeutic strategy directly targeting fibroblasts is lacking. Nitric oxide-mediated nitrosative stress is associated with cardiac injury, and excessive nitric oxide can trigger S-nitrosylation (SNO) to specific cysteine thiol. This study aims to investigate the role of SNO in cardiac fibrosis and to identify potential therapeutic target. METHODS:SNO proteomic analysis was performed in cardiac tissue isolated from both mice subjected to transverse aortic constriction and spontaneous hypertensive rats. Elevated SNO of pyruvate kinase M2 (PKM2) was identified in cardiac fibroblasts, which was merely detected in cardiomyocytes. Cardiac fibroblast-specific PKM2 knockout mice and mice transfected with wild-type or SNO-resistant PKM2 mutant were used to determine the involvement of SNO of PKM2 (SNO-PKM2) in cardiac fibrosis. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to explore effectors mediating SNO-PKM2-induced activation of cardiac fibroblasts. A recently approved drug for rare blood disorder, mitapivat, was shown to dose-dependently relieve cardiac fibrosis. RESULTS:SNO of PKM2 at cysteine 49 and 326 increased in the heart tissue of patients with heart failure, heart tissue of murine cardiac fibrosis models, and cardiac fibroblasts stimulated with angiotensin II. SNO-PKM2 reduced pyruvate kinase activity and tetramerization of PKM2, and cardiac fibroblast-specific PKM2 knockout aggravated cardiac fibrosis, whereas cardiac fibroblast-specific PKM2 knockout mice transfected with SNO-resistant mutant rather than wild-type PKM2 had cardiac function. Mechanistically, SNO-PKM2 drove excessive mitochondrial fission and mitochondrial dysfunction through interfering with its interaction with actin regulatory protein gelsolin. TEPP-46, a pharmacological PKM2 activator, alleviated mitochondrial fission and cardiac fibrosis. Moreover, the US Food and Drug Administration-approved drug mitapivat showed preventive and therapeutical effects on cardiac fibrosis through activating PKM2. CONCLUSIONS:SNO-PKM2 specifically increases in cardiac fibroblasts and activated cardiac fibroblasts by inducing excessive mitochondrial fission through a gelsolin-dependent manner. Mitapivat is a potential therapeutic option for attenuating cardiac fibrosis.

BACKGROUND:Obesity is a well-documented cardiovascular risk factor. Here, we sought to investigate whether obesity causes subclinical cardiac remodeling and heart failure (HF), and if so, to perform a systematic scan of the plasma protein for novel drug targets. METHODS:We leveraged visceral adipose tissue (VAT), waist circumference (WC), and waist-to-hip ratio (WHR)-all adjusted for body mass index (BMI)-as indicators of obesity. Two-sample Mendelian randomization (MR) analyses were used to estimate the independent, causal effects of obesity on cardiovascular magnetic resonance (CMR)-derived cardiac traits and HF risk. Mediation analyses followed by druggability assessment were conducted to identify promising protein targets for therapeutic translation. RESULTS:Genetically determined VATadjBMI, WCadjBMI, and WHRadjBMI presented broad causal associations with alterations of distinct cardiac phenotypes, most of which remained significant after controlling for obesity-induced cardiometabolic risk factors, including hypertension, type 2 diabetes, and adverse lipid profiles. By contrast, WHRadjBMI is the only independent causal predictor for HF risk. Of 142 proteins with mediating effects, scavenger receptor class A member 5 (SCARA5), membrane cofactor protein (CD46), and alpha-1-antichymotrypsin (SERPINA3) may contribute to the early-stage adverse cardiovascular effect of obesity, whereas apolipoprotein C-III (APOC3), mitochondrial aldehyde dehydrogenase 2 (ALDH2), and chordin-like protein 2 (CHRDL2) may further promote the development of obesity-driven HF. Medications targeted at these candidate proteins are either approved or under evaluation in clinical trials. CONCLUSIONS:Our MR findings provided genetic evidence for the direct, causal associations of obesity with cardiac remodeling and HF, while also outlining druggable proteins as promising therapeutic targets.

Large-scale characterization of gut viral genomes provides strain-resolved insights into host-microbe interactions. However, existing viral genomes are mainly derived from Western populations, limiting our understanding of global gut viral diversity and functional variations necessary for personalized medicine and addressing regional health disparities. Here, we introduce the Chinese Gut Viral Reference (CGVR) set, consisting of 120,568 viral genomes from 3234 deeply sequenced fecal samples collected nationwide, covering 72,751 viral operational taxonomic units (vOTUs), nearly 90 Our analysis underscores the unique genetic makeup of the gut virome across populations and emphasizes the importance of recognizing gut viral genetic heterogeneity for deeper insights into regional health implications.