Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities

Circulation Research, Journal Year: 2024, Volume and Issue: 134(12), P. 1718 - 1751

Published: June 6, 2024

The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory fibrogenic cascades that ultimately result in formation a scar. After infarction, massive cardiomyocyte death releases broad range damage-associated molecular patterns initiate both myocardial systemic responses. TLRs (toll-like receptors) NLRs (NOD-like recognize (DAMPs) transduce downstream proinflammatory signals, leading to upregulation cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], interleukin-6) chemokines CCL2 [CC chemokine ligand 2]) recruitment neutrophils, monocytes, lymphocytes. Expansion diversification cardiac macrophages infarcted play major role clearance infarct from dead cells subsequent stimulation reparative pathways. Efferocytosis triggers induction release anti-inflammatory mediators restrain reaction set stage for fibroblasts vascular cells. Growth factor–mediated pathways, neurohumoral cascades, matricellular proteins deposited provisional matrix stimulate fibroblast proliferation myofibroblast conversion. Deposition well-organized collagen-based extracellular network protects catastrophic rupture attenuates ventricular dilation. Scar maturation requires signals inhibit activity prevent excessive fibrosis. Moreover, mature scar, neovessels acquire mural cell coat contributes stabilization microvascular network. Excessive, prolonged, or dysregulated accentuate adverse remodeling dysfunction. leukocytes can contribute arrhythmogenesis. Inflammatory pathways may be promising therapeutic targets attenuate failure progression arrhythmia generation patients surviving infarction.

Language: Английский

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Macrophages promote the transition from myocardial ischemia reperfusion injury to cardiac fibrosis in mice through GMCSF/CCL2/CCR2 and phenotype switching

Acta Pharmacologica Sinica, Journal Year: 2024, Volume and Issue: 45(5), P. 959 - 974

Published: Jan. 15, 2024

Language: Английский

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From Iron Metabolism to Ferroptosis: Pathologic Changes in Coronary Heart Disease

Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 14

Published: Aug. 10, 2022

Coronary heart disease (CHD) is closely related to oxidative stress and inflammatory response the most common cardiovascular (CVD). Iron an essential mineral that participates in many physiological biochemical reactions human body. Meanwhile, on negative side, iron has active redox capacity, which leads accumulation of reactive oxygen species (ROS) lipid peroxidation. There growing evidence disordered metabolism involved CHD’s pathological progression. And result associated with overload-induced programmed cell death, often called ferroptosis. That features iron-dependent Ferroptosis may play a crucial role development CHD, targeting ferroptosis be promising option for treating CHD. Here, we review mechanisms cardiomyocytes (CMs) explain correlation between highlight specific roles main progression

Language: Английский

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Cardiac Fibrosis in heart failure: Focus on non-invasive diagnosis and emerging therapeutic strategies

Molecular Aspects of Medicine, Journal Year: 2023, Volume and Issue: 93, P. 101194 - 101194

Published: June 27, 2023

Heart failure is a leading cause of mortality and hospitalization worldwide. Cardiac fibrosis, resulting from the excessive deposition collagen fibers, common feature across spectrum conditions converging in heart failure. Eventually, either reparative or reactive nature, long-term cardiac fibrosis contributes to development progression associated with poor clinical outcomes. Despite this, specific antifibrotic therapies are lacking, making an urgent unmet medical need. In this context, better patient phenotyping needed characterize heterogenous features advance toward its personalized management. review, we will describe different phenotypes focus on potential usefulness imaging techniques circulating biomarkers for non-invasive characterization condition tracking impact. We also recapitulate effects existing non-heart drugs discuss strategies under preclinical targeting activation fibroblasts at levels, as well additional extracardiac processes.

Language: Английский

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Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: March 28, 2023

Cardiac fibrosis plays an indispensable role in cardiac tissue homeostasis and repair after myocardial infarction (MI). The fibroblast-to-myofibroblast differentiation extracellular matrix collagen deposition are the hallmarks of fibrosis, which modulated by multiple signaling pathways various types cells time-dependent manners. Our understanding development MI has evolved basic clinical researches, regulation fibrotic remodeling may facilitate novel diagnostic therapeutic strategies, finally improve outcomes. Here, we aim to elaborate pathophysiology, examination intervention MI.

Language: Английский

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The Microenvironment of the Pathogenesis of Cardiac Hypertrophy

Cells, Journal Year: 2023, Volume and Issue: 12(13), P. 1780 - 1780

Published: July 4, 2023

Pathological cardiac hypertrophy is a key risk factor for the development of heart failure and predisposes individuals to arrhythmia sudden death. While physiological adaptive, resulting from conditions comprising hypertension, aortic stenosis, or genetic mutations, such as hypertrophic cardiomyopathy, maladaptive. Here, we highlight essential role reciprocal interactions involving both cardiomyocytes non-myocardial cells in response pathological conditions. Prolonged cardiovascular stress causes enter an activated state releasing numerous pro-hypertrophic, pro-fibrotic, pro-inflammatory mediators vasoactive hormones, growth factors, cytokines, i.e., commencing signaling events that collectively cause hypertrophy. Fibrotic remodeling mediated by fibroblasts central players, but also endothelial resident infiltrating immune enhance these processes. Many are now being integrated into computational models provide system-level insights will help translate our knowledge new pharmacological targets. This perspective article summarizes last decades' advances research discusses herein-involved complex myocardial microenvironment components.

Language: Английский

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Deciphering the fibrotic process: mechanism of chronic radiation skin injury fibrosis

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 15, 2024

This review explores the mechanisms of chronic radiation-induced skin injury fibrosis, focusing on transition from acute radiation damage to a fibrotic state. It reviewed cellular and molecular responses radiation, highlighting role myofibroblasts significant impact Transforming Growth Factor-beta (TGF-β) in promoting fibroblast-to-myofibroblast transformation. The delves into epigenetic regulation gene expression, contribution extracellular matrix proteins microenvironment, immune system context fibrosis. Additionally, it discusses potential biomaterials artificial intelligence medical research advance understanding treatment suggesting future directions involving bioinformatics personalized therapeutic strategies enhance patient quality life.

Language: Английский

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Heart‐on‐a‐Chip Model of Epicardial–Myocardial Interaction in Ischemia Reperfusion Injury

Advanced Healthcare Materials, Journal Year: 2024, Volume and Issue: 13(21)

Published: April 29, 2024

Epicardial cells (EPIs) form the outer layer of heart and play an important role in development disease. Current heart-on-a-chip platforms still do not fully mimic native cardiac environment due to absence relevant cell types, such as EPIs. Here, using Biowire II platform, engineered tissues with epicardial inner myocardial structure are constructed, image analysis approach is developed track EPI migration a beating environment. Functional properties improve over two weeks culture. In conditions mimicking ischemia reperfusion injury (IRI), experience less death lower impact on functional properties. coverage significantly reduced more diffuse under normoxic compared post-IRI conditions. Upon IRI, into tissue interior observed, contributions alpha smooth muscle actin positive population. Altogether, novel model designed incorporate EPIs through formation process that mimics development, this work demonstrates respond differently than epicardium-free controls, highlighting importance including constructs aim accurately

Language: Английский

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Nitro-oleic acid alleviates inflammation and fibrosis by regulating macrophage polarization and fibroblast activation to improve cardiac function in MI mice

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 146, P. 113710 - 113710

Published: Jan. 1, 2025

Chronic heart failure, caused by myocardial fibrosis after acute infarction (AMI), remains a serious clinical problem that needs urgent resolution. Nitro-oleic acid (OA-NO2), an electrophilic nitro-fatty found in human plasma, is believed to regulate various pathophysiological functions, particularly anti-inflammation and anti-fibrosis. However, the role of OA-NO2 AMI unexplored. Thus, our aim was investigate whether could ameliorate post-myocardial fibrosis, improve cardiac function, elucidate its mechanism mice. In vivo experiments involved constructing mice model administering via subcutaneous osmotic minipumps. Echocardiography transmission electron microscope indicated can alleviate injury systolic function. Transcriptomics tissue suggested improved fibrosis. Immunohistochemistry qPCR results demonstrated OA-NO2's reduction accumulation extracellular matrix (Collagen I Collagen III). vitro showed remarkably suppressed activation fibroblasts myofibroblast transition induced transforming growth factor-β (TGF-β). Furthermore, inhibited expression α-SMA, collagen I, III TGF-β/smad2/3 signaling pathway. Immunofluorescence ELISA detection revealed not only alleviated but also reduced inflammation decreased inflammatory factors (TNF-α, IL-1β, IL-6, MCP-1). Mechanistically, significantly polarization LPS-induced macrophages into M1-type inhibiting NF-κB (P65) related pathways. Therefore, postmyocardial function myofibroblasts M1 macrophages.

Language: Английский

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Bioinformatics-Based Exploration of the Ability of Ginkgetin to Alleviate the Senescence of Cardiomyocytes After Myocardial Infarction and Its Cardioprotective Effects

Journal of Inflammation Research, Journal Year: 2025, Volume and Issue: Volume 18, P. 301 - 323

Published: Jan. 1, 2025

Myocardial infarction (MI) is a prevalent cardiovascular disorder affecting individuals worldwide. There need to identify more effective therapeutic agents minimize cardiomyocyte damage and enhance cardioprotection. Bioinformatics analysis was performed predict the underlying biological mechanisms of ginkgetin in treatment MI. Next, we further validation through experiments. For vivo studies, used coronary ligation construct an MI rat model. In vitro, oxygen glucose deprivation (OGD) simulate ischemia H9c2 cardiomyocytes. revealed that key targets for were MMP2, MMP9, VEGFA. Immune infiltration might be involved immune regulation by acting on TCR signaling pathway. The results GO enrichment protect heart cell membrane alleviate senescent apoptosis cardiomyocytes after studies ameliorated myocardial pathological cardiac decompensation It also alleviated inflammatory Additionally, can downregulate activation signals pathway dephosphorylating CD3 CD28. vitro attenuated elevated OGD-induced cytotoxicity, increased viability, apoptosis, thus protecting Ginkgetin inhibits postinfarction fibrosis hypertrophy, scavenges free radicals, decreases limbic infiltration, suppresses inflammatory-immune pathway, delays peripheral cells from undergoing heart.

Language: Английский

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