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Researchers develop a heart ‘fingerprint’ to tailor personalised treatments.
N-terminal cysteine acetylation and oxidation patterns may define protein stability.
Oxygen homeostasis is maintained in plants and animals by O2-sensing enzymes initiating adaptive responses to low O2 (hypoxia). Recently, the O2-sensitive enzyme ADO was shown to initiate degradation of target proteins RGS4/5 and IL32 via the Cysteine/Arginine N-degron pathway. ADO functions by catalysing oxidation of N-terminal cysteine residues, but despite multiple proteins in the human proteome having an N-terminal cysteine, other endogenous ADO substrates have not yet been identified. This could be because alternative modifications of N-terminal cysteine residues, including acetylation, prevent ADO-catalysed oxidation. Here we investigate the relationship between ADO-catalysed oxidation and NatA-catalysed acetylation of a broad range of protein sequences with N-terminal cysteines. We present evidence that human NatA catalyses N-terminal cysteine acetylation in vitro and in vivo. We then show that sequences downstream of the N-terminal cysteine dictate whether this residue is oxidised or acetylated, with ADO preferring basic and aromatic amino acids and NatA preferring acidic or polar residues. In vitro, the two modifications appear to be mutually exclusive, suggesting that distinct pools of N-terminal cysteine proteins may be acetylated or oxidised. These results reveal the sequence determinants that contribute to N-terminal cysteine protein modifications, with implications for O2-dependent protein stability and the hypoxic response.
Nitric oxide biosensor uncovers diminished ferrous iron-dependency of cultured cells adapted to physiological oxygen levels.
Iron is an essential metal for cellular metabolism and signaling, but it has adverse effects in excess. The physiological consequences of iron deficiency are well established, yet the relationship between iron supplementation and pericellular oxygen levels in cultured cells and their downstream effects on metalloproteins has been less explored. This study exploits the metalloprotein geNOps in cultured HEK293T epithelial and EA.hy926 endothelial cells to test the iron-dependency in cells adapted to standard room air (18 kPa O2) or physiological normoxia (5 kPa O2). We show that cells in culture require iron supplementation to activate the metalloprotein geNOps and demonstrate for the first time that cells adapted to physiological normoxia require significantly lower iron compared to cells adapted to hyperoxia. This study establishes an essential role for recapitulating oxygen levels in vivo and uncovers a previously unrecognized requirement for ferrous iron supplementation under standard cell culture conditions to achieve geNOps functionality.
Hif-2α programs oxygen chemosensitivity in chromaffin cells.
The study of transcription factors that determine specialized neuronal functions has provided invaluable insights into the physiology of the nervous system. Peripheral chemoreceptors are neurone-like electrophysiologically excitable cells that link the oxygen concentration of arterial blood to the neuronal control of breathing. In the adult, this oxygen chemosensitivity is exemplified by type I cells of the carotid body, and recent work has revealed one isoform of the hypoxia-inducible transcription factor (HIF), HIF-2α, as having a nonredundant role in the development and function of that organ. Here, we show that activation of HIF-2α, including isolated overexpression of HIF-2α but not HIF-1α, is sufficient to induce oxygen chemosensitivity in adult adrenal medulla. This phenotypic change in the adrenal medulla was associated with retention of extra-adrenal paraganglioma-like tissues resembling the fetal organ of Zuckerkandl, which also manifests oxygen chemosensitivity. Acquisition of chemosensitivity was associated with changes in the adrenal medullary expression of gene classes that are ordinarily characteristic of the carotid body, including G protein regulators and atypical subunits of mitochondrial cytochrome oxidase. Overall, the findings suggest that, at least in certain tissues, HIF-2α acts as a phenotypic driver for cells that display oxygen chemosensitivity, thus linking 2 major oxygen-sensing systems.
Immune-mediated cardiac development and regeneration.
The complex interplay between the immune and cardiovascular systems during development, homeostasis and regeneration represents a rapidly evolving field in cardiac biology. Single cell technologies, spatial mapping and computational analysis have revolutionised our understanding of the diversity and functional specialisation of immune cells within the heart. From the earliest stages of cardiogenesis, where primitive macrophages guide heart tube formation, to the complex choreography of inflammation and its resolution during regeneration, immune cells emerge as central orchestrators of cardiac fate. Translating these fundamental insights into clinical applications represents a major challenge and opportunity for the field. In this Review, we decode the immunological blueprint of heart development and regeneration to transform cardiovascular disease treatment and unlock the regenerative capacity of the human heart.
MicroRNA-210 Enhances Cell Survival and Paracrine Potential for Cardiac Cell Therapy While Targeting Mitophagy.
The therapeutic potential of presumed cardiac progenitor cells (CPCs) in heart regeneration has garnered significant interest, yet clinical trials have revealed limited efficacy due to challenges in cell survival, retention, and expansion. Priming CPCs to survive the hostile hypoxic environment may be key to enhancing their regenerative capacity. We demonstrate that microRNA-210 (miR-210), known for its role in hypoxic adaptation, significantly improves CPC survival by inhibiting apoptosis through the downregulation of Casp8ap2, a ~40% reduction in caspase activity, and a ~90% decrease in DNA fragmentation. Contrary to the expected induction of Bnip3-dependent mitophagy by hypoxia, miR-210 did not upregulate Bnip3, indicating a distinct anti-apoptotic mechanism. Instead, miR-210 reduced markers of mitophagy and increased mitochondrial biogenesis and oxidative metabolism, suggesting a role in metabolic reprogramming. Furthermore, miR-210 enhanced the secretion of paracrine growth factors from CPCs, with a ~1.6-fold increase in the release of stem cell factor and of insulin growth factor 1, which promoted in vitro endothelial cell proliferation and cardiomyocyte survival. These findings elucidate the multifaceted role of miR-210 in CPC biology and its potential to enhance cell-based therapies for myocardial repair by promoting cell survival, metabolic adaptation, and paracrine signalling.
[Associations of plasma metabolites with mortality in Chinese adults: a prospective study].
Objective: To investigate the prospective associations between plasma metabolites and the risks of all-cause and cause-specific mortality among Chinese adults. Methods: This study analyzed plasma metabolomics data from 2 183 healthy adults in the China Kadoorie Biobank (CKB), measured using targeted mass spectrometry. Cox proportional hazards regression models were used to examine the associations between 630 metabolites and the risk of all-cause mortality. Cause-specific hazard regression models evaluated the associations between metabolites and cardiovascular disease (CVD) risks, cancer, and other-cause mortality. Stepwise regression was used to identify key metabolites independently associated with all-cause mortality, and the area under the receiver operating characteristic curve (AUC) was calculated to assess the improvement in predictive performance when these metabolites were added to traditional risk prediction models. Results: The mean age of the participants was (53.2±9.8) years, 65.1% of whom were female. During a median follow-up of 14.5 years, 231 deaths occurred. A total of 44 metabolites were significantly associated with the risk of all-cause mortality [false discovery rate (FDR)-adjusted P<0.05], primarily including triglycerides, ceramides, and amino acids. Additionally, 29 and 15 metabolites were found to be associated with cancer and other-cause mortality, respectively, but no metabolites were significantly associated with CVD mortality after FDR corrections. Adding 14 metabolites independently associated with all-cause mortality into the traditional prediction model significantly improved its predictive performance. Specifically, incorporating metabolites into the traditional model, which already included laboratory biomarkers, increased the AUC to 0.798 (95%CI: 0.755-0.843), an improvement of 0.088 compared to the traditional model (P<0.001). Conclusions: Multiple metabolites are significantly associated with mortality risk and can substantially improve the accuracy of mortality risk prediction models. These findings provide new insights into the physiological mechanisms of aging and offer valuable clues for personalized health risk assessment.
Exercise Improves Myocardial Deformation But Not Cardiac Structure in Preterm-Born Adults: A Randomized Clinical Trial.
BACKGROUND: People born preterm (<37 weeks' gestation) have a potentially adverse cardiac phenotype that progresses with blood pressure elevation. OBJECTIVES: The authors investigated whether preterm-born and term-born adults exhibit similar cardiac structural and functional remodeling following a 16-week aerobic exercise intervention. METHODS: We conducted a randomized controlled trial in 203 adults (aged 18-35 years) with elevated blood pressure or stage 1 hypertension. Participants were randomized 1:1 to a 16-week aerobic exercise intervention or to a control group. In a prespecified cardiovascular magnetic resonance imaging (CMR) substudy, CMR was performed at 3.0-Tesla to assess left and right ventricular (LV and RV) structure and function before and after intervention. RESULTS: A total of 100 participants completed CMR scans at baseline and after the 16-week intervention, with n = 47 in the exercise intervention group (n = 26 term-born; n = 21 preterm-born) and n = 53 controls (n = 32 term-born; n = 21 preterm-born). In term-born participants, LV mass to end-diastolic volume ratio decreased (-3.43; 95% CI: -6.29 to -0.56; interaction P = 0.027) and RV stroke volume index increased (5.53 mL/m2; 95% CI: 2.60, 8.47; interaction P = 0.076) for those in the exercise intervention group vs controls. No significant effects were observed for cardiac structural indices in preterm-born participants. In preterm-born participants, LV basal- and mid-ventricular circumferential strain increased (-1.33; 95% CI: -2.07 to -0.60; interaction P = 0.057 and -1.54; 95% CI: -2.46 to -0.63; interaction P = 0.046, respectively) and RV global longitudinal strain increased (1.99%; 95% CI: -3.12 to -0.87; interaction P = 0.053) in the exercise intervention group vs controls. No significant effects were observed for myocardial deformation parameters in term-born participants. CONCLUSIONS: Aerobic exercise training induces improved myocardial function but not cardiac structure in preterm-born adults.
Proteome-Wide Genetic Study in East Asians and Europeans Identified Multiple Therapeutic Targets for Ischemic Stroke.
BACKGROUND: Analyses of genomic and proteomics data in prospective biobank studies in diverse populations may discover novel or repurposing drug targets for stroke. METHODS: We extracted individual cis-protein quantitative trait locus for 2923 proteins measured using Olink Explore panel from a genome-wide association study in prospective China Kadoorie Biobank and UK Biobank, both established ≈20 years ago. These cis-protein quantitative trait loci were used in ancestry-specific 2-sample Mendelian randomization analyses of ischemic stroke (IS) in East Asians (n=22 664 cases) and Europeans (n=62 100 cases). We further undertook colocalization analyses to examine the shared causal variants of cis-protein quantitative trait locus with stroke, along with various downstream analyses (eg, phenome-wide association study, drug development lookups) to clarify mechanisms of action and druggability. RESULTS: In Mendelian randomization analyses, the genetically predicted plasma levels of 10 proteins were significantly associated with IS in East Asians (n=2) and Europeans (n=9), with 6 proteins (FGF5 [fibroblast growth factor 5], TMPRSS5 [transmembrane protease serine 5], FURIN, F11 [coagulation factor XI], ALDH2 [aldehyde dehydrogenase 2], and ABO) showing positive and 4 (GRK5 [G protein-coupled receptor kinase 5], KIAA0319 [dyslexia-associated protein KIAA0319], PROCR [endothelial protein C receptor], and MMP12 [macrophage metalloelastase 12]) showing inverse associations, all directionally consistent between East Asians and Europeans. Colocalization analyses provided strong evidence (posterior probabilities for the H4 hypothesis ≥0.7) of shared genetic variants with IS for 9 out of 10 proteins (except ABO). Moreover, 8 proteins were also causally associated, in the expected directions, with systolic blood pressure (positive/inverse: 4/2), low-density lipoprotein cholesterol (1 positive), body mass index (1 inverse), type 2 diabetes (2/1), or atrial fibrillation (3/1). Phenome-wide association study analyses and lookups in knock-out mouse models confirmed their importance for IS or stroke-related traits (eg, hematologic phenotypes). Of these 10 proteins, 1 was not druggable (ABO), 3 had known primary (F11) or potentially repurposed (ALDH2, MMP12) drug targets for stroke, and 6 (PROCR, GRK5, FGF5, FURIN, KIAA0319, and TMPRSS5) had no evidence of any drug targets. CONCLUSIONS: Proteogenomic investigation in diverse ancestry populations identified the causal relevance of 10 proteins for IS, with several being potentially novel or repurposed targets that could be prioritized for further investigation.
HCM-Associated MuRF1 Variants Compromise Ubiquitylation and Are Predicted to Alter Protein Structure
MuRF1 [muscle RING (Really Interesting New Gene)-finger protein-1] is an ubiquitin-protein ligase (E3), which encode by TRIM63 (tripartite motif containing 63) gene, playing a crucial role in regulating cardiac muscle size and function through ubiquitylation. Among hypertrophic cardiomyopathy (HCM) patients, 24 TRIM63 variants have been identified, with 1 additional variant linked to restrictive cardiomyopathy. However, only three variants have been previously investigated for their functional effects. The structural impacts of the 25 variants remain unexplored. This study investigated the effects of 25 MuRF1 variants on ubiquitylation activity using in vitro ubiquitylation assays and structural predictions using computational approaches. The variants were generated using site-directed PCR (Polymerase Chain Reaction) mutagenesis and subsequently purified with amylose affinity chromatography. In vitro ubiquitylation assays demonstrated that all 25 variants compromised the ability of MuRF1 to monoubiquitylate a titin fragment (A168-A170), while 17 variants significantly impaired or completely abolished auto-monoubiquitylation. Structural modelling predicted that 10 MuRF1 variants disrupted zinc binding or key stabilising interactions, compromising structural integrity. In contrast, three variants were predicted to enhance the structural stability of MuRF1, while six others were predicted to have no discernible impact on the structure. This study underscores the importance of functional assays and structural predictions in evaluating MuRF1 variant pathogenicity and provides novel insights into mechanisms by which these variants contribute to HCM and related cardiomyopathies.
Stroke risk management in carotid atherosclerotic disease: a clinical consensus statement of the ESC Council on Stroke and the ESC Working Group on Aorta and Peripheral Vascular Diseases.
Carotid atherosclerotic disease continues to be an important cause of stroke, often disabling or fatal. Such strokes could be largely prevented through optimal medical therapy and carotid revascularization. Advancements in discovery research and imaging along with evidence from recent pharmacology and interventional clinical trials and registries and the progress in acute stroke management have markedly expanded the knowledge base for clinical decisions in carotid stenosis. Nevertheless, there is variability in carotid-related stroke prevention and management strategies across medical specialities. Optimal patient care can be achieved by (i) establishing a unified knowledge foundation and (ii) fostering multi-specialty collaborative guidelines. The emergent Neuro-Vascular Team concept, mirroring the multi-disciplinary Heart Team, embraces diverse specializations, tailors personalized, stratified medicine approaches to individual patient needs, and integrates innovative imaging and risk-assessment biomarkers. Proposed approach integrates collaboration of multiple specialists central to carotid artery stenosis management such as neurology, stroke medicine, cardiology, angiology, ophthalmology, vascular surgery, endovascular interventions, neuroradiology, and neurosurgery. Moreover, patient education regarding current treatment options, their risks and advantages, is pivotal, promoting patient's active role in clinical care decisions. This enables optimization of interventions ranging from lifestyle modification, carotid revascularization by stenting or endarterectomy, as well as pharmacological management including statins, novel lipid-lowering and antithrombotic strategies, and targeting inflammation and vascular dysfunction. This consensus document provides a harmonized multi-specialty approach to multi-morbidity prevention in carotid stenosis patients, based on comprehensive knowledge review, pinpointing research gaps in an evidence-based medicine approach. It aims to be a foundational tool for inter-disciplinary collaboration and prioritized patient-centric decision-making.