Fibroblast and myofibroblast activation in normal tissue repair and fibrosis

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(8), P. 617 - 638

Published: April 8, 2024

Language: Английский

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Properties and Functions of Fibroblasts and Myofibroblasts in Myocardial Infarction

Cells, Journal Year: 2022, Volume and Issue: 11(9), P. 1386 - 1386

Published: April 20, 2022

The adult mammalian heart contains abundant interstitial and perivascular fibroblasts that expand following injury play a reparative role but also contribute to maladaptive fibrotic remodeling. Following myocardial infarction, cardiac undergo dynamic phenotypic transitions, contributing the regulation of inflammatory, reparative, angiogenic responses. This review manuscript discusses mechanisms regulation, roles fate in infarcted heart. During inflammatory phase infarct healing, release alarmins by necrotic cells promotes pro-inflammatory matrix-degrading fibroblast phenotype may leukocyte recruitment. clearance dead matrix debris from stimulates anti-inflammatory pathways activates transforming growth factor (TGF)-β cascades, resulting conversion α-smooth muscle actin (α-SMA)-expressing myofibroblasts. Activated myofibroblasts secrete large amounts proteins form collagen-based scar protects ventricle catastrophic complications, such as rupture. Moreover, repair stimulating angiogenesis. maturation, disassemble α-SMA+ stress fibers convert specialized serve maintenance. prolonged activation border zone remote remodeling myocardium adverse pathogenesis failure. In addition their plasticity, exhibit remarkable heterogeneity. Subsets with distinct profiles be responsible for wide range functions populations hearts.

Language: Английский

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Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 31, 2024

Abstract The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate system, macrophages play an essential initial inflammatory that occurs following injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, diverse phenotypes and phenotypic alterations strongly associate with distinct types severity diseases, including coronary heart disease, valvular myocarditis, cardiomyopathy, failure, atherosclerosis aneurysm, which underscores importance investigating macrophage regulatory mechanisms within context specific diseases. Besides, recent strides single-cell sequencing technologies have revealed heterogeneity, cell–cell interactions, downstream therapeutic targets at higher resolution, brings new perspectives into macrophage-mediated potential Remarkably, myocardial fibrosis, prevalent characteristic most cardiac remains formidable clinical challenge, necessitating profound investigation impact on fibrosis In this review, we systematically summarize functional plasticity diseases unprecedented insights introduced by technologies, focus different causes characteristics especially relationship between inflammation (myocardial infarction, pressure overload, dilated diabetic cardiomyopathy aging) vascular injury (atherosclerosis aneurysm). Finally, highlight preclinical/clinical targeting strategies translational implications.

Language: Английский

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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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The signaling pathways of selected traditional Chinese medicine prescriptions and their metabolites in the treatment of diabetic cardiomyopathy: a review

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

Published: July 3, 2024

Diabetic cardiomyopathy (DCM) is a myocardial-specific microvascular disease caused by diabetes that affects the structure and function of heart considered to be leading cause morbidity death in patients with diabetes. Currently, there no specific treatment or preventive drug for DCM, an urgent need develop new drugs treat DCM. Traditional Chinese medicine (TCM) has rich experience its characteristics multi-target, multi-pathway, multi-component, few side effects can effectively deal complexity long-term nature Growing evidence suggests myocardial fibrosis, inflammation, oxidative stress, apoptosis, cardiac hypertrophy, advanced glycation end product deposition were main pathologic mechanisms According pathological mechanism this study revealed potential metabolites prescriptions TCM against DCM from perspective signaling pathways. The results showed TGF-β/Smad, NF-κB, PI3K/AKT, Nrf2, AMPK, NLRP3, Wnt/β-catenin pathways key aim was summarize update screen targets candidates provide ideas more experimental clinical use

Language: Английский

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Chromatin remodelling drives immune cell–fibroblast communication in heart failure

Nature, Journal Year: 2024, Volume and Issue: 635(8038), P. 434 - 443

Published: Oct. 23, 2024

Language: Английский

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Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy

Journal of Clinical Investigation, Journal Year: 2025, Volume and Issue: 135(1)

Published: Jan. 1, 2025

Loss of Bcl2-associated athanogene 3 (BAG3) is associated with dilated cardiomyopathy (DCM). BAG3 regulates sarcomere protein turnover in cardiomyocytes; however, the function other cardiac cell types understudied. In this study, we used an isogenic pair BAG3-knockout and wild-type human induced pluripotent stem cells (hiPSCs) to interrogate role hiPSC-derived fibroblasts (CFs). Analysis type-specific conditional knockout engineered heart tissues revealed essential contribution CF contractility fibrosis, recapitulating phenotype DCM. BAG3-/- CFs, observed increased sensitivity TGF-β signaling activation a fibrogenic response when cultured at physiological stiffness (8 kPa). Mechanistically, showed that loss transforming growth factor-β receptor 2 (TGFBR2) levels by directly binding TGFBR2 mediating its ubiquitination proteasomal degradation. To further validate these results, performed single-nucleus RNA sequencing tissue from DCM patients carrying pathogenic variants. variants fibrotic gene expression CFs. Together, results extend our understanding roles disease beyond cardiomyocyte-centric view highlight ability tissue-engineered hiPSC models elucidate aspects disease.

Language: Английский

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Luteolin ameliorates rat model of metabolic syndrome-induced cardiac injury by apoptosis suppression and autophagy promotion via NR4A2/p53 regulation

BMC Complementary Medicine and Therapies, Journal Year: 2025, Volume and Issue: 25(1)

Published: Jan. 20, 2025

Reduced cardiac autophagy, inflammation, and apoptosis contribute to cardiovascular complications caused by metabolic syndrome (MetS). It is documented that the nuclear receptor 4A2 (NR4A2) could modulate autophagy in complications. The aim of this investigation was assess therapeutic potential luteolin, with beneficial properties, against MetS-associated injury. Forty male albino Wistar rats were divided into 5 groups randomly as controls, MetS, MetS animals treated luteolin (25, 50, 100 mg/kg ip). animal's weight, blood pressure, lipid profile, tolerance glucose insulin, histopathology evaluated. Moreover, troponin T, creatine kinase-myocardial band (CK-MB), inflammatory profile (IL-6, IL-1β, TNF-α), transforming growth factor-β1 (TGF-β1), oxidative stress, matrix metalloproteinase-9 (MMP-9) analyzed determine state. Cardiac NR4A2 p53, well apoptotic (B-cell leukemia/lymphoma 2 [BCL-2], Caspase [CASP]-3, CASP-9) autophagic mediators (Sequestosome-1/p62, Microtubule-associated protein 1 A/1B-light chain 3 [LC3], Beclin-1) measured RT-qPCR ELISA. Luteolin remarkably restored MetS-induced biochemical derangements related injury via suppression apoptosis, stress but promotion (p-value < 0.001). Current findings revealed promising therapeutical properties risks.

Language: Английский

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Macrophages in myocardial infarction

AJP Cell Physiology, Journal Year: 2022, Volume and Issue: 323(4), P. C1304 - C1324

Published: Sept. 12, 2022

The heart contains a population of resident macrophages that markedly expands following injury through recruitment monocytes and proliferation macrophages. In myocardial infarction, have been implicated in both injurious reparative responses. coronary atherosclerotic lesions, disease progression the pathogenesis plaque rupture. Following contribute to initiation regulation inflammatory response. Phagocytosis efferocytosis are major functions during phase infarct healing, mediate phenotypic changes, leading acquisition an anti-inflammatory macrophage phenotype. Infarct respond changes cytokine content extracellular matrix composition their environment secrete fibrogenic angiogenic mediators, playing central role repair infarcted heart. Macrophages may also play scar maturation chronic adverse remodeling noninfarcted segments. Single cell studies revealed remarkable heterogeneity populations hearts; however, relations between transcriptomic profiles functional properties remain poorly defined. This review manuscript discusses fate, mechanisms expansion activation, Considering critical injury, repair, remodeling, important, but challenging, targets for therapeutic interventions infarction.

Language: Английский

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Emerging Antiarrhythmic Drugs for Atrial Fibrillation

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(8), P. 4096 - 4096

Published: April 7, 2022

Atrial fibrillation (AF), the most common cardiac arrhythmia worldwide, is driven by complex mechanisms that differ between subgroups of patients. This complexity apparent from different forms in which AF presents itself (post-operative, paroxysmal and persistent), each with heterogeneous patterns variable progression. Our current understanding responsible for initiation, maintenance progression has increased significantly recent years. Nevertheless, antiarrhythmic drugs management have not been developed based on underlying none currently used were specifically to target AF. With knowledge AF, new opportunities developing more effective safer therapies are emerging. In this review, we provide an overview potential novel approaches focusing both development agents possibility repurposing already marketed drugs. addition, discuss opportunity targeting some key players involved mechanisms, such as ryanodine receptor type-2 (RyR2) channels atrial-selective K+-currents (IK2P ISK) therapy. highlight components inflammatory signaling (e.g., NLRP3-inflammasome) upstream fibroblast function prevent structural remodeling Finally, critically appraise emerging drug principles future directions development, well their improving management.

Language: Английский

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