Overexpression of ABCA1 in Carotid Endothelium of Hyperlipidemic Rabbits Modulates Vascular Inflammation

Human Gene Therapy, Год журнала: 2025, Номер unknown

Опубликована: Март 20, 2025

Endothelial activation and dysfunction are key early steps in atherogenesis. Vascular gene therapy targeting endothelial inflammation cholesterol accumulation could decrease atherosclerosis progression. ATP-binding cassette subfamily A member 1 (ABCA1) exhibits anti-inflammatory properties promotes efflux. mouse model showed that systemic overexpression of ABCA1 decreased diet-induced atherosclerosis. To test if local protects against atherosclerosis, we used helper-dependent adenoviral vectors (HDAd) to express or a "Null" control the carotid endothelium hyperlipidemic rabbits. Both mRNA protein were increased 3 days after vector infusion. After 24 weeks on high-fat diet, laser-microdissected expression, but whole-vessel was with HDAdABCA1. not be measured at weeks, so its may transient. CD68 expression (-23%, p < 0.001), ITGAM (-15%, = 0.3) unchanged. Macrophage markers for both M1-like macrophages (IL1B: -44% [p 0.02]; IL6: -40% CCL2: -25% 0.02]) M2-like (ARG1: -27% 0.03]; IL10: -23% 0.09]; TGFB1: -13% 0.001]) also decreased. The inflammatory cytokines IL6 (-100%; 0.001) TNF (p 0.05) significantly endothelium, VCAM1 (+5%, 1.0) unchanged ICAM1 (+101%; 0.03) increased. Lesion size, intimal lipid, macrophage content all > 0.5 all), vascular by mass spectrometry (-11%; 0.9) no difference. There small intimal/medial ratio. scRNAseq revealed transcripts restricted cells 24+ detected most cell types. exception modulated smooth muscle cells, which found substantial numbers larger lesions. Overall, transient subtly alters markers, providing only modest atheroprotection.

Язык: Английский

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Human Tendon‐on‐a‐Chip for Modeling the Myofibroblast Microenvironment in Peritendinous Fibrosis

Advanced Healthcare Materials, Год журнала: 2024, Номер 14(4)

Опубликована: Ноя. 15, 2024

Understanding the myofibroblast microenvironment is critical to developing therapies for fibrotic diseases. Here development of a novel human tendon-on-a-chip (hToC) reported model this crosstalk in peritendinous adhesions, which currently lacks biological therapies. The hToC facilitates cellular and paracrine interactions between vascular component, contains endothelial cells monocytes, tissue hydrogel component that houses tendon macrophages. It found replicates some aspects vivo inflammatory phenotypes preclinical clinical samples, including activated mTOR signaling, inflammation, contraction induced by activation, cytokines secretion, transendothelial migration monocytes hydrogel. Transcriptional analysis demonstrates significant overlap enriched pathways with tenolysis activation signaling. Rapamycin suppresses inflammation phenotype hToC, provides proof-of-concept its utility as an vitro tool investigating multicellular fibrosis testing therapeutics mitigate it.

Язык: Английский

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Oxygen–ozone therapy for myocardial ischemic stroke and cardiovascular disorders

Medical Gas Research, Год журнала: 2024, Номер unknown

Опубликована: Авг. 31, 2024

Cardiovascular diseases (CVDs) represent a major concern for human health worldwide. Emergencies in this field include wide repertories of studies dealing primarily with CVD prevention. In addition to dietary habits and lifestyles, medical knowledge is fully needed improve public educational programs toward cardiovascular risk factors enrich the endowment pharmaceutical options therapies address CVDs, particularly ischemic damage due an impairment endothelial–myocardial relationship. Because ozone stimulator endothelial nitric oxide synthase/nitric pathway, therapy has been widely demonstrated have ability counteract endothelial-cardiac disorders, providing novel straightforward opportunity reduce impact including atrial fibrillation. review, we attempt establish state-of-the-art method use CVD, suggesting that future remarks be addressed provide fundamental insights into issue. The purpose study was highlight role adjunctive treatment pathologies such as acute myocardial infarction disorders.

Язык: Английский

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Chemokine Fractalkine and Non-Obstructive Coronary Artery Disease—Is There a Link?

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3885 - 3885

Опубликована: Март 30, 2024

Non-obstructive coronary artery disease (NO-CAD) constitutes a heterogeneous group of conditions collectively characterized by less than 50% narrowing in at least one major with fractional flow reserve (FFR) ≤0.80 observed angiography. The pathogenesis and progression NO-CAD are still not fully understood, however, inflammatory processes, particularly atherosclerosis microvascular dysfunction known to play role it. Chemokine fractalkine (FKN/CX3CL1) is inherently linked these processes. FKN/CX3CL1 functions predominantly as chemoattractant for immune cells, facilitating their transmigration through the vessel wall inhibiting apoptosis. Its concentrations correlate positively cardiovascular risk factors. Moreover, promising preliminary results have shown that receptor inhibitor (KAND567) administered population patients ST-elevation myocardial infarction (STEMI) undergoing percutaneous intervention (PCI), inhibits adverse reaction system causes hyperinflammation. Whereas link between appears evident, further studies necessary unveil this complex relationship. In review, we critically overview current data on context present novel clinical implications unique structure function compound which distinctively contributes pathomechanism condition.

Язык: Английский

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Cracking the code of the cardiovascular enigma: hPSC-derived endothelial cells unveil the secrets of endothelial dysfunction

Journal of Molecular and Cellular Cardiology, Год журнала: 2024, Номер 192, С. 65 - 78

Опубликована: Май 16, 2024

Язык: Английский

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Success of Nitric Oxide System Modulators in Pharmacocorrection of Some Indicators of Endothelial Dysfunction After Intrauterine Hypoxia

Опубликована: Ноя. 4, 2024

Prenatal hypoxia plays a crucial role in programming long-term cardiovascular dysfunction through mechanisms like endothelial and nitric oxide system impairment, highlighting the potential of therapeutic agents, such as thiotriazoline, angiolin, mildronate, L-arginine, for mitigating these adverse effects. Methods. Levels sEPCR, Tie2 tyrosine kinase, VEGF-B, SOD1/Cu-Zn SOD, GPX4, GPX1 were measured heart&#039;s cytosolic homogenate using ELISA. Results. Modeling prenatal (PH) resulted significant alterations concentrations proteins linked to function oxidative stress heart cytosol experimental animals, including an increase sEPCR reductions Tie-2, Cu/ZnSOD, levels. Postnatal administration modulators (L-arginine, mildronate) demonstrated differential efficacy normalizing proteins. Notably, angiolin produced most substantial effect, restoring Tie2, antioxidant enzyme levels near-normal Our results highlight Angiolin Thiotriazoline car-diovascular following hypoxia, supporting their early postnatal in-terventions prevent dysfunction.

Язык: Английский

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Cardiomyocyte and stromal cell cross-talk influences the pathogenesis of arrhythmogenic cardiomyopathy: a multi-level analysis uncovers DLK1-NOTCH pathway role in fibro-adipose remodelling

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Ноя. 28, 2024

Abstract Arrhythmogenic Cardiomyopathy (ACM) is a life-threatening, genetically determined disease primarily caused by mutations in desmosomal genes, such as PKP2 . Currently, there no etiological therapy for ACM due to its complex and not fully elucidated pathogenesis. Various cardiac cell types affected the genetic mutation, cardiomyocytes (CM) mesenchymal stromal cells (cMSC), individually contribute phenotype, driving functional abnormalities fibro-fatty substitution, respectively. However, relative importance of CM cMSC alterations, well their reciprocal influence progression remain poorly understood. We hypothesised that ACM-dependent phenotypes are driven only alterations individual but also interactions between cMSC, which may further impact utilized patient-specific, multicellular system composed either control or -mutated assess mutation’s role phenotype immunofluorescence, contractile behaviour co-cultures using motion detection software. Additionally, we investigated both silico via multi-targeted proteomics. demonstrated can promote fibro-adipose differentiation cMSC. Conversely, increasing rate abnormal events with likely arrhythmic significance. Furthermore, showed an ACM-causative mutation alters CM-cMSC interaction pattern. identified CM-sourced DLK1 novel regulator remodelling ACM. Our study challenges paradigm exclusive cell-specific mechanisms A deeper understanding cell-cell crucial identifying therapeutic targets ACM, this concept exploitable other cardiomyopathies.

Язык: Английский

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Protective effect of UDCA against IL-11- induced cardiac fibrosis is mediated by TGR5 signalling

Frontiers in Cardiovascular Medicine, Год журнала: 2024, Номер 11

Опубликована: Дек. 3, 2024

Cardiac fibrosis occurs in a wide range of cardiac diseases and is characterised by the transdifferentiation fibroblasts into myofibroblasts these cells produce large quantities extracellular matrix, resulting myocardial scar. The profibrotic process multi-factorial, meaning identification effective treatments has been limited. antifibrotic effect bile acid ursodeoxycholic (UDCA) established cases liver however its mechanism role less well understood.

Язык: Английский

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Pathogenesis of cardiovascular diseases: effects of mitochondrial CF6 on endothelial cell function

Molecular and Cellular Biochemistry, Год журнала: 2024, Номер unknown

Опубликована: Июль 10, 2024

Язык: Английский

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Molecular Mechanisms of the Failing Heart: A Fatal Regression?

Journal of Asian Pacific Society of Cardiology, Год журнала: 2024, Номер 3

Опубликована: Июнь 13, 2024

Heart failure (HF) is one of the most common causes death, and number HF patients increasing worldwide due to population ageing. The pathogenesis has been extensively studied by many researchers with a focus on cardiomyocytes, but its complex pathophysiology yet be elucidated. Non-cardiomyocytes account for >70% cells that comprise heart, there close communication between non-cardiomyocytes suggesting might play pivotal role in development HF. Neurohumoral factors, such as autonomic nerves hormones, regulate heart’s function. Conversely, heart affects other organs through blood perfusion, underscoring importance interorgan communication. This review discusses HF, topic not explored.

Язык: Английский

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