Acylations are post-translational modifications in which functional groups are attached to amino acids on proteins. Most acylations (acetylation, butyrylation, crotonylation, lactylation, malonylation, propionylation and...Acylations are post-translational modifications in which functional groups are attached to amino acids on proteins. Most acylations (acetylation, butyrylation, crotonylation, lactylation, malonylation, propionylation and succinylation) involve lysine but cysteine (palmitoylation) and glycine (myristoylation) residues can also be altered. Acylations have important roles in physiological and pathophysiological processes, including cardiac hypertrophy and related cardiovascular diseases. These post-translational modifications influence chromatin architecture, transcriptional regulation and metabolic pathways, thereby affecting cardiomyocyte function and pathology. The dynamic interaction between these acylations and their regulatory enzymes, such as histone acetyltransferases, histone deacetylases and sirtuins, underscores the complexity of cellular homeostasis and pathological processes. Emerging evidence highlights the therapeutic potential of targeting acylations to modulate enzyme activity and metabolite levels, offering promising avenues for novel treatments. In this Review, we explore the diverse mechanisms through which acylations contribute to cardiac hypertrophy, highlighting the complexity and potential therapeutic targets in this regulatory network.
Irreversible cardiac fibrosis, cardiomyocyte death and chronic cardiac dysfunction after myocardial infarction pose a substantial global health-care challenge, with no curative treatments available. To regenerate the inj...Irreversible cardiac fibrosis, cardiomyocyte death and chronic cardiac dysfunction after myocardial infarction pose a substantial global health-care challenge, with no curative treatments available. To regenerate the injured heart, cardiomyocytes must proliferate to replace lost myocardial tissue - a capability that adult mammals have largely forfeited to adapt to the demanding conditions of life. Using various preclinical models, our understanding of cardiomyocyte proliferation has progressed remarkably, leading to the successful reactivation of cell cycle induction in adult animals, with functional recovery after cardiac injury. Central to this success is the targeting of key pathways and structures that drive cardiomyocyte maturation after birth - nucleation and ploidy, sarcomere structure, developmental signalling, chromatin and epigenetic regulation, the microenvironment and metabolic maturation - forming a complex regulatory framework that allows efficient cellular contraction but restricts cardiomyocyte proliferation. In this Review, we explore the molecular pathways underlying these core mechanisms and how their manipulation can reactivate the cell cycle in cardiomyocytes, potentially contributing to cardiac repair.
Nat Rev Cardiol
· 2025 Nov · PMID 40175709
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Clonal haematopoiesis is the clonal expansion of blood stem cells with acquired mutations. Clonal haematopoiesis of indeterminate potential (CHIP), traditionally defined as clonal haematopoiesis driven by a pre-leukaemic...Clonal haematopoiesis is the clonal expansion of blood stem cells with acquired mutations. Clonal haematopoiesis of indeterminate potential (CHIP), traditionally defined as clonal haematopoiesis driven by a pre-leukaemic mutation in at least 2% of sequenced alleles, affects 10-20% of individuals aged >70 years. Although CHIP is considered a precursor condition for haematological malignancies, population-based data suggest that the majority of CHIP-associated mortality is attributable to non-malignant conditions, such as cardiovascular disease. Observational human studies have shown that CHIP is a strong and independent predictor of the onset and progression of atherosclerotic cardiovascular disease, heart failure and arrhythmia. In addition, findings from animal experiments suggest that CHIP is causally involved in these diseases and might be a risk factor that can be targeted with therapeutics. As our understanding of the cardiovascular implications of CHIP and other types of clonal haematopoiesis rapidly expands, it has become increasingly clear that clonal haematopoiesis subtypes have substantial heterogeneity with respect to magnitude of effect and underlying mechanisms for different cardiovascular diseases. In this Review, we discuss clonal haematopoiesis as a prognostic factor for numerous cardiovascular diseases, highlight its potential as a therapeutic target and propose a potential role for CHIP in cardiovascular precision medicine.
Therapeutic anticoagulation is essential to prevent and treat venous and arterial thromboembolism. The available agents target coagulation factors involved in thrombus formation but are associated with an increased risk...Therapeutic anticoagulation is essential to prevent and treat venous and arterial thromboembolism. The available agents target coagulation factors involved in thrombus formation but are associated with an increased risk of bleeding. Factor XI plays a minor role in haemostasis but contributes substantially to thrombus expansion, making it an attractive target to mitigate bleeding while maintaining antithrombotic efficacy. Various novel inhibitors, including antisense oligonucleotides, monoclonal antibodies and small molecules, have been developed. Phase II trials in orthopaedic surgery showed dose-dependent reductions in venous thromboembolism without significantly increasing bleeding compared with enoxaparin. In the first phase III trial of a small-molecule inhibitor of activated factor XI in patients with atrial fibrillation, asundexian was associated with a reduction in bleeding but also a higher risk of stroke, compared with apixaban. Factor XI inhibitors appear safe and hold promise for secondary prevention in myocardial infarction and ischaemic stroke, with ongoing phase III trials assessing their broader efficacy and safety. This Review discusses the rationale, pharmacology, evidence and future directions of factor XI inhibitors across various clinical settings.
Mitochondria are multifunctional organelles that are important for many different cellular processes, including energy production and biosynthesis of fatty acids, haem and iron-sulfur clusters. Mitochondrial dysfunction...Mitochondria are multifunctional organelles that are important for many different cellular processes, including energy production and biosynthesis of fatty acids, haem and iron-sulfur clusters. Mitochondrial dysfunction leads to a disruption in these processes, the generation of excessive reactive oxygen species, and the activation of inflammatory and cell death pathways. The consequences of mitochondrial dysfunction are particularly harmful in energy-demanding organs such as the heart. Loss of terminally differentiated cardiomyocytes leads to cardiac remodelling and a reduced ability to sustain contraction. Therefore, cardiomyocytes rely on multilayered mitochondrial quality control mechanisms to maintain a healthy population of mitochondria. Mitochondrial chaperones protect against protein misfolding and aggregation, and resident proteases eliminate damaged proteins through proteolysis. Irreparably damaged mitochondria can also be degraded through mitochondrial autophagy (mitophagy) or ejected from cells inside vesicles. The accumulation of dysfunctional mitochondria in cardiomyocytes is a hallmark of ageing and cardiovascular disease. This accumulation is driven by impaired mitochondrial quality control mechanisms and contributes to the development of heart failure. Therefore, there is a strong interest in developing therapies that directly target mitochondrial quality control in cardiomyocytes. In this Review, we discuss the current knowledge of the mechanisms involved in regulating mitochondrial quality in cardiomyocytes, how these pathways are altered with age and in disease, and the therapeutic potential of targeting mitochondrial quality control pathways in cardiovascular disease.
Communication between multicellular organs is essential to propagate signals and coordinate their function. Over the past decade, the role of extracellular vesicles in the molecular communication between cells in both ph...Communication between multicellular organs is essential to propagate signals and coordinate their function. Over the past decade, the role of extracellular vesicles in the molecular communication between cells in both physiological and pathological settings has received much attention. Extracellular vesicles can shuttle proteins, lipids and nucleic acids (such as RNA) between cells, thus inducing an array of functional changes in the recipient cells. In this Review, we describe the different extracellular vesicle subclasses and their heterogeneous nature, provide insights into extracellular vesicle-mediated signalling in the cardiovascular system, and highlight how extracellular vesicles can be used as diagnostic and prognostic biomarkers for a variety of pathological conditions. Finally, we also discuss the potential therapeutic applications of extracellular vesicles.
The neural and cardiovascular systems are pivotal in regulating human physiological, cognitive and emotional states, constantly interacting through anatomical and functional connections referred to as the brain-heart axi...The neural and cardiovascular systems are pivotal in regulating human physiological, cognitive and emotional states, constantly interacting through anatomical and functional connections referred to as the brain-heart axis. When this axis is dysfunctional, neurological conditions can lead to cardiovascular disorders and, conversely, cardiovascular dysfunction can substantially affect brain health. However, the mechanisms and fundamental physiological components of the brain-heart axis remain largely unknown. In this Review, we elucidate these components and identify three primary pathways: neural, mechanical and biochemical. The neural pathway involves the interaction between the autonomic nervous system and the central autonomic network in the brain. The mechanical pathway involves mechanoreceptors, particularly those expressing mechanosensitive Piezo protein channels, which relay crucial information about blood pressure through peripheral and cerebrovascular connections. The biochemical pathway comprises many endogenous compounds that are important mediators of neural and cardiovascular function. This multisystem perspective calls for the development of integrative approaches, leading to new clinical specialties in neurocardiology.
Endomyocardial fibrosis, first described >75 years ago, is a cause of restrictive cardiomyopathy with an unclear aetiopathogenesis that is most commonly found in children and adolescents from tropical regions of Africa,...Endomyocardial fibrosis, first described >75 years ago, is a cause of restrictive cardiomyopathy with an unclear aetiopathogenesis that is most commonly found in children and adolescents from tropical regions of Africa, Asia and South America. The epidemiological trends of this cardiomyopathy are difficult to ascertain. The characteristic hallmark of endomyocardial fibrosis is ventricular fibrosis that causes diastolic dysfunction and atrioventricular regurgitation. Although advances in medical treatment for heart failure and more tailored surgical techniques to treat the condition have increased survival, the outcomes in affected patients remain poor. A major focus of research is the identification of biomarkers of preclinical disease and new therapeutic targets. Collaborative multidisciplinary research and cross-learning from other fibrotic conditions should impart knowledge and help to improve the survival rates and the quality of life of patients with endomyocardial fibrosis.
Masenga SK, Wandira N, Cattivelli-Murdoch G
… +7 more, Saleem M, Beasley H, Hinton A, Ertuglu LA, Mwesigwa N, Kleyman TR, Kirabo A
Nat Rev Cardiol
· 2025 Sep · PMID 39984695
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Full text
Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular disease in individuals with or without hypertension. However, the mechanisms and management of SSBP remain unclear, mainly becaus...Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular disease in individuals with or without hypertension. However, the mechanisms and management of SSBP remain unclear, mainly because the diagnosis of this condition relies on salt loading-depletion protocols that are not feasible in the clinic. The prevalence of hypertension is lower in premenopausal women than in men, but this sex-specific difference is reversed after menopause. Whether excessive SSBP in women at any age contributes to this reversal is unknown, but many clinical studies that have rigorously assessed for SSBP using salt loading-depletion protocols have confirmed that SSBP is more prevalent in women than in men, including during premenopausal age. In this Review, we discuss sex-specific mechanisms of SSBP. We describe sex-related differences in renal transporters, hypertensive pregnancy, SSBP in autoimmune disorders and mitogen-activated protein kinase signalling pathways, and highlight limitations and lessons learned from Dahl salt-sensitive rat models.
Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulato...Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.