Myocardial ischemia/reperfusion: Translational pathophysiology of ischemic heart disease

Med, Journal Year: 2024, Volume and Issue: 5(1), P. 10 - 31

Published: Jan. 1, 2024

Ischemic heart disease is the greatest health burden and most frequent cause of death worldwide. Myocardial ischemia/reperfusion pathophysiological substrate ischemic disease. Improvements in prevention treatment have reduced mortality developed countries over last decades, but further progress now stagnant, morbidity from developing are increasing. Significant problems remain to be resolved require a better understanding. The present review attempts briefly summarize state art myocardial research, with view on both its coronary vascular aspects, define cutting edges where mechanistic knowledge needed facilitate translation clinical practice.

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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Endothelial cells drive organ fibrosis in mice by inducing expression of the transcription factor SOX9

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(736)

Published: Feb. 28, 2024

Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it unclear to what extent endothelial cells also might contribute. We detected increased expression the transcription factor Sox9 in several different mouse fibrosis models. These models included systolic heart failure induced by pressure overload, diastolic high-fat diet and nitric oxide synthase inhibition, pulmonary bleomycin treatment, liver due choline-deficient diet. observed up-regulation SOX9 cardiac tissue from patients with failure. To test whether induction was sufficient cause disease, we generated mice cell–specific overexpression , which promoted multiple organs resulted signs Endothelial deletion prevented organ dysfunction two as well lung Bulk single-cell RNA sequencing across vascular beds revealed that extracellular matrix, growth factor, inflammatory gene expression, leading matrix deposition cells. Moreover, activated neighboring then migrated deposited response SOX9, process partly mediated secreted CCN2, direct target; reversed these changes. findings suggest role for fibrosis-promoting during disease imply an important regulator fibrosis.

Language: Английский

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Protein glycosylation in cardiovascular health and disease

Nature Reviews Cardiology, Journal Year: 2024, Volume and Issue: 21(8), P. 525 - 544

Published: March 18, 2024

Language: Английский

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Specialized pericyte subtypes in the pulmonary capillaries

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Pericytes are essential for capillary stability and homeostasis, with impaired pericyte function linked to diseases like pulmonary arterial hypertension. Investigating biology has been challenging due the lack of specific markers, making it difficult distinguish pericytes from other stromal cells. Using bioinformatic analysis RNAscope, we identified Higd1b as a unique gene marker subsequently generated knock-in mouse line, -CreERT2, that accurately labels in lung heart. Single-cell RNA sequencing revealed two distinct + subtypes: while Type 1 support 2 accumulate arterioles, co-express smooth muscle markers higher levels vimentin under hypoxic conditions. Lastly, healthy human upregulation exhibited increased adhesion, migration, expression SM22 vitro. These findings highlight specialization their contribution vascular remodeling during hypoxia-induced

Language: Английский

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TGF-β as a therapeutic target in the infarcted and failing heart: cellular mechanisms, challenges, and opportunities

Expert Opinion on Therapeutic Targets, Journal Year: 2024, Volume and Issue: 28(1-2), P. 45 - 56

Published: Feb. 1, 2024

Introduction Myocardial fibrosis accompanies most cardiac conditions and can be reparative or maladaptive. Transforming Growth Factor (TGF)-β is a potent fibrogenic mediator, involved in repair, remodeling, of the injured heart.

Language: Английский

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Glycoprotein 130 Antagonism Counteracts Metabolic and Inflammatory Alterations to Enhance Right Ventricle Function in Pulmonary Artery Banded Pigs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Right ventricular dysfunction (RVD) is a risk factor for death in multiple cardiovascular diseases, but RV-enhancing therapies are lacking. Inhibition of glycoprotein-130 (GP130) signaling with the small molecule SC144 improves RV function rodent RVD via anti-inflammatory and metabolic mechanisms. However, SC144's efficacy molecular effects translational large animal model unknown. 4-week-old castrated male pigs underwent pulmonary artery banding (PAB). After 3 weeks, PAB were randomized into 2 groups (daily injections [2.2 mg/kg, PAB-SC144, n =5] or vehicle [PAB-Veh, weeks). Five age-matched served as controls. Cardiac MRI quantified size/function. heart catheterization evaluated hemodynamics. Single-nucleus RNA sequencing delineated cell-type specific changes between experimental groups. Electron microscopy mitochondrial morphology. Phosphoproteomics identified dysregulated kinases. Lipidomics metabolomics lipid species metabolites tissue. Quantitative proteomics examined protein regulation. significantly improved ejection fraction (Control: 60±4%, PAB-Veh: 22±10%, PAB-SC144: 37±6%) despite similar afterload. demonstrated PAB-Veh had lower cardiomyocyte higher macrophage/lymphocyte/pericyte/endothelial cell abundances compared to control, many these blunted by SC144. combatted downregulation genes induced PAB. Kinome enrichment analysis suggested counteracted mTORC1 activation. Correspondingly, rebalanced autophagy pathway proteins Integrated lipidomics, metabolomics, analyses revealed restored fatty acid metabolism. Finally, CellChat pericyte-endothelial cross-talk. GP130 antagonism blunts elevated immune abundance, reduces pro-inflammatory gene transcription macrophages lymphocytes, rebalances preserves metabolism cardiomyocytes, restores endothelial pericyte communication improve function.

Language: Английский

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Pericytes in the brain and heart: functional roles and response to ischaemia and reperfusion

Cardiovascular Research, Journal Year: 2024, Volume and Issue: unknown

Published: July 26, 2024

In the last 20 years there has been a revolution in our understanding of how blood flow is regulated many tissues. Whereas it used to be thought that essentially all control occurred at arteriole level, now recognised capillary by contractile pericytes plays key role both regulating physiologically and reducing clinically-relevant pathological conditions. this article we compare contrast brain cardiac regulate cerebral coronary flow, focusing mainly on events ischemia. The beds differ dramatically morphology, yet cases pericyte-mediated constriction restricting after ischemia possibly other We conclude with suggestions for therapeutic approaches relaxing pericytes, which may prove useful long term pericyte-induced

Language: Английский

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Protective role of the longevity-associated BPIFB4 gene on cardiac microvascular cells and cardiac aging

Vascular Pharmacology, Journal Year: 2025, Volume and Issue: 158, P. 107470 - 107470

Published: Feb. 3, 2025

In recent years, the role of cardiac microvasculature in modulating symptoms and disease progression patients affected by pathology has been reconsidered. The term microvascular (CMD) describes set functional and/or structural alterations that reduce ability heart to adequately increase its coronary blood flow keep up with increased metabolic demand. CMD is involved evolution both ischemic non-ischemic origin as well aging. primary actors this process are cells stromal compartment, whose nature biology now investigated a new level detail thanks single-cell omics studies. Recent studies on genetics extreme longevity have identified polymorphic haplotype variant BPIFB4 gene confers prolonged life span health span, atheroprotective advantages, an improved immune response. aim review was focus beneficial effects longevity-associated (LAV) cell biology, providing novel exciting mechanisms action directed against development or many age-related cardiovascular diseases, thus emphasizing translational therapeutic potential.

Language: Английский

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Disease pathogenicity in Hutchinson–Gilford progeria syndrome mice: insights from lung-associated alterations

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: March 24, 2025

Abstract Background Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by accelerated aging, impaired growth, disrupted lipid metabolism, and reduced lifespan. Methods Prior research has primarily focused on cardiovascular manifestations, our sheds light multiple organs that underwent significant age-related changes validated tissue cross-sections H&E, Masson's trichrome, β-galactosidase staining. Results Among these pathologies tissues, the lung was severely affected substantiated clinical data of pulmonary anomalies from HGPS patients. Biochemical histological analyses mouse model revealed elevated Progerin expression, abnormal NAD cellular senescence markers (higher level p16 p27, lower ki67), various morphology changes, including fibrosis, inflammation, thickening alveolar walls. Transcriptomic indicated down-regulated genes ( Thy1 , Tnc Cspg4 Ccr1 ) were associated with extracellular space, immune response, calcium signaling pathway, osteoclast differentiation, binding pathway. Conclusions This study unveiled previously overlooked involved in pathogenesis suggested specific emphasis lung. Our findings suggest abnormalities may contribute to disease progression, warranting further investigation into their role monitoring management. Graphical abstract

Language: Английский

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