Blood-borne sphingosine 1-phosphate maintains vascular resistance and cardiac function.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 19, 2025

Abstract G protein-coupled receptors (GPCRs) are key regulators of cardiovascular function that provide targets for the treatment disease. Sphingosine 1-phosphate (S1P) is an erythrocyte- and platelet-derived lipid mediator with cognate GPCRs on endothelial cells (EC), vascular smooth muscle (VSMC) cardiomyocytes. S1P circulates in plasma bound to apolipoprotein M (ApoM)-containing high-density lipoproteins (HDL) albumin. Circulating levels correlate positively systolic blood pressure hypertension negatively severity septic shock left ventricular (LV) coronary heart In mice, impaired binding HDL or signaling EC both trigger hypertension, supporting essential role HDL-S1P function. The roles albumin-S1P myocyte S1PRs homeostasis remain incompletely defined. Contrasting isolated deficiency, we report non-selective depletion circulating pools mice impairs LV contractile induces hypotension resistance spontaneous increase age. Cardiac output was preserved naïve deficient by compensatory dilation, but cardiac reserve reduced a dobutamine stress test. These phenotypes tracked hematopoietic cell production were partially fully reversed erythrocyte transfusion. Hypotension accompanied peripheral resistance, infusion dose-dependently increased perfused kidneys from wild-type not compound deficiency S1PR2&3. Epistatic analysis supported critical S1PR3 S1P-dependent regulation pointed distinct origin phenotype. Although elevated hypertensive humans, increasing sufficient induce naive mice. observations suggests crosses endothelium arteries gain access VSMC receptors, S1PR maintenance They also highlight chaperones specifying responses relevance as biomarker potential therapeutic target failure.

Язык: Английский

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Regenerative therapies for myocardial infarction: exploring the critical role of energy metabolism in achieving cardiac repair

Frontiers in Cardiovascular Medicine, Год журнала: 2025, Номер 12

Опубликована: Фев. 7, 2025

Cardiovascular diseases are the most lethal worldwide, of which myocardial infarction is leading cause death. After infarction, in order to ensure normal blood supply heart, remaining cardiomyocytes compensate for loss mainly by working at high capacity rather than proliferating produce new cardiomyocytes. This partly due extremely limited ability adult heart repair itself. A growing body research suggests that cardiac regenerative closely related metabolic shifts energy sources. Currently, a large number studies have focused on changes levels before and after proliferation window cardiomyocytes, so it crucial search relevant factors pathways regulate cell cycle cardiomyocyte progression. paper presents review role metabolism injury. It aims elucidate effects mammals point out directions regeneration clinical treatment infarction.

Язык: Английский

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Transcriptional, proteomic and metabolic drivers of cardiac regeneration

Heart, Год журнала: 2025, Номер unknown, С. heartjnl - 325442

Опубликована: Март 4, 2025

Following injury, many organs are capable of rapid regeneration necrotic tissue to regain normal function. In contrast, the damaged heart typically replaces with a collagen-rich scar, due limited regenerative capacity its functional contractile cardiomyocytes (CMs). However, this varies dramatically during development and between species. Furthermore, studies have shown that cardiac can be enhanced return function following myocardial infarction (MI). review, we outline proliferative CMs in utero, postnatally adulthood. We also describe MI injury. Finally, focus on various therapeutic strategies aim augment preclinical animal models. These include altering transcripts, microRNAs, extracellular matrix proteins inducing metabolic rewiring. Together, these therapies potentially improve lives millions failure patients currently suffering worldwide.

Язык: Английский

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Molecular gatekeepers of endogenous adult mammalian cardiomyocyte proliferation

Nature Reviews Cardiology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 7, 2025

Язык: Английский

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Cell cycle arrest of cardiomyocytes in the context of cardiac regeneration

Frontiers in Cardiovascular Medicine, Год журнала: 2025, Номер 12

Опубликована: Апрель 28, 2025

The limited capacity of adult mammalian cardiomyocytes to undergo cell division and proliferation is one the key factors contributing heart failure. In newborn mice, cardiac occurs during a brief window, but this proliferative diminishes by 7 days after birth. Current studies on regeneration focused elucidating changes in regulatory within before aiming determine whether potential association between these cycle arrest cardiomyocytes. Facilitating re-entry into or reversing their exit from it represents critical strategy for regeneration. This paper provides an overview role regeneration, briefly describes cardiomyocyte systematically summarizes regulation cardiomyocytes, metabolic mechanisms underlying arrest. Additionally, we highlight development cardiovascular disease drugs targeting status clinical treatment. Our goal outline strategies promoting repair following injury, while also pointing toward future research directions that may offer new technologies prospects treating diseases, such as myocardial infarction, arrhythmia

Язык: Английский

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Sphingosine‐1‐phosphate signalling in the heart: exploring emerging perspectives in cardiopathology

FEBS Letters, Год журнала: 2024, Номер 598(21), С. 2641 - 2655

Опубликована: Июль 4, 2024

Cardiometabolic disorders contribute to the global burden of cardiovascular diseases. Emerging sphingolipid metabolites like sphingosine‐1‐phosphate (S1P) and its receptors, S1PRs, present a dynamic signalling axis significantly impacting cardiac homeostasis. S1P's intricate mechanisms extend transportation in bloodstream by two specific carriers: high‐density lipoprotein particles albumin. This transport system ensures accessibility S1P distant target tissues, influencing several physiological processes critical for health. review delves into diverse functions S1PRs both pathophysiological conditions heart. Emphasis is placed on their roles modulating health, spanning from contractility, angiogenesis, inflammation, atherosclerosis myocardial infarction. The interplays involving receptors are analysed concerning different cell types, shedding light respective heart We also therapeutic applications targeting S1P/S1PRs diseases, considering existing drugs Fingolimod, as well prospects challenges developing novel therapies that selectively modulate S1PRs.

Язык: Английский

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CXCL4 deficiency limits M4 macrophage infiltration and attenuates hyperoxia-induced lung injury

Molecular Medicine, Год журнала: 2024, Номер 30(1)

Опубликована: Дек. 20, 2024

Язык: Английский

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Cardiomyocyte‐Specific Overexpression of Activated Yes‐Associated Protein Modified‐RNA Promotes Cardiomyocyte Proliferation and Myocardial Regeneration

Journal of the American Heart Association, Год журнала: 2024, Номер unknown

Опубликована: Окт. 29, 2024

Background The proliferative capacity of cardiomyocytes in adult mammalian hearts is far too low to replace the cells that are lost myocardial infarction. Both cardiomyocyte proliferation and regeneration can be improved via overexpression a constitutively active variant YAP5SA (Yes‐associated protein, 5SA [active] mutant), but persistent proliferation‐inducing genes could lead hypertrophy arrhythmia, whereas off‐target expression fibroblasts macrophages increase fibrosis inflammation. Methods Results Transient or GFP (green fluorescent protein; control) was targeted our cardiomyocyte‐specific modified mRNA translation system ( CM‐SMRTs CM‐SMRTs, respectively). YAP5SA‐cardiomyocyte specificity confirmed vitro experiments cardiac had been differentiated from human induced‐ pluripotent stem umbilical‐vein endothelial cells, regenerative potency evaluated mouse infarction model. In cultured induced‐pluripotent cells‐cardiomyocytes, YAP abundantly expressed for 3 days after administration accompanied by increases markers proliferation, before declining near‐background levels day 7, fluorescence remained high 1 treatment then slowly declined. also observed cells‐cardiac on declined substantially 3. model, echocardiographic assessments left‐ventricular ejection fraction fractional shortening were significantly greater, infarct sizes smaller CM‐SMRTs–treated mice than vehicle‐treated control animals, appeared promote proliferation. Conclusions used transiently specifically overexpress cardiomyocytes, this strategy promoted

Язык: Английский

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Effects and mechanisms of the myocardial microenvironment on cardiomyocyte proliferation and regeneration

Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12

Опубликована: Июль 10, 2024

The adult mammalian cardiomyocyte has a limited capacity for self-renewal, which leads to the irreversible heart dysfunction and poses significant threat myocardial infarction patients. In past decades, research efforts have been predominantly concentrated on proliferation regeneration. However, is complex organ that comprises not only cardiomyocytes but also numerous noncardiomyocyte cells, all playing integral roles in maintaining cardiac function. addition, are exposed dynamically changing physical environment includes oxygen saturation mechanical forces. Recently, growing number of studies microenvironment regeneration ongoing. this review, we provide an overview recent advances microenvironment, plays important role

Язык: Английский

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Nisin A elevates adenosine to achieve anti-inflammatory activity

Food & Function, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

This study uncovers that nisin A achieves excellent anti-inflammatory activity via enhancing the level of adenosine, followed by up-regulation sphingolipid signaling pathway and down-regulation purine metabolism.

Язык: Английский

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