Cardiovascular dysfunction and altered lysosomal signaling in a murine model of acid sphingomyelinase deficiency

Journal of Molecular Medicine, Год журнала: 2025, Номер unknown

Опубликована: Апрель 15, 2025

Язык: Английский

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ACLY Promotes Cardiac Fibrosis via the Regulation of DNL and Histone Acetylation

Hypertension, Год журнала: 2025, Номер unknown

Опубликована: Март 6, 2025

ATP citrate lyase (ACLY) is a key enzyme in de novo lipogenesis that generates acetyl-CoA from citrate. Although fatty acids are required for energy production and biomass synthesis the heart, regulatory mechanisms of ACLY-mediated pathological cardiac fibroblasts remain unknown. The aim this study was to investigate biological role ACLY remodeling. Adeno-associated virus serotype 9-mediated shRNA targeting Acly intravenously injected into C57BL/6J male mice. mice were subsequently continuously infused with mixture angiotensin II phenylephrine. Cardiac phenotypes evaluated via histological staining. Cell proliferation assays, stable isotope tracing 13C-labeled glucose, chromatin immunoprecipitation assays performed using human fibroblasts. expression upregulated heart sections treated II/phenylephrine, particular fibrotic areas. Masson trichrome staining revealed gene silencing significantly reduced fibrosis these Both siRNA-mediated knockdown pharmacological inhibition suppressed fibrous proteins cultured stimulated transforming growth factor-β. Mechanistically, lipogenesis, limiting acid supply essential cellular proliferation. It also decreased H3K9 H3K27 acetylation, addition presence acetylated at promoter regions genes. Our findings demonstrate plays an important maladaptive fibrosis. could be novel therapeutic target prevent development failure.

Язык: Английский

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MMP3 as a new target of Danshensu/tetramethylpyrazine derivative for attenuating cardiac fibrosis post-myocardial infarction

Life Sciences, Год журнала: 2025, Номер unknown, С. 123570 - 123570

Опубликована: Март 1, 2025

Язык: Английский

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Cardiovascular Dysfunction and Altered Lysosomal Signaling in a Murine Model of Acid Sphingomyelinase Deficiency

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 20, 2025

Niemann-Pick Disease (NPD) is a rare autosomal recessive lysosomal storage disorder (LSD) caused by the deficiency of acid sphingomyelinase (ASMD), which encoded Smpd1 gene. ASMD impacts multiple organ systems in body, including cardiovascular system. This study first to characterize cardiac pathological changes mice under baseline conditions, offering novel insights into implications NPD. Using histological analysis, biochemical assays, and echocardiography, we assessed function Smpd1^−/− compared Smpd1^+/+ littermate controls. Immunofluorescence assays demonstrated that induced dysfunction, as evidenced accumulation lysosomal-associated membrane proteins, protease, autophagosomes pericytes cardiomyocytes. dysfunction was accompanied cardiomyocytes inflammation, characterized increased expression caspase1 inflammatory cytokines, infiltration cells tissues mice. In addition, analysis revealed lipid deposition steatosis, along with pericyte-to-myofibroblast transition (PMT) interstitial fibrosis Moreover, echocardiography further developed coronary microvascular (CMD), decreased blood flow velocity arteriolar wall thickness. Additionally, these exhibited significant impairments systolic diastolic function, shown reduced ejection fraction prolonged left ventricular relaxation time constant (Tau value). These findings suggest induces profound vascular myocardium, potentially driven mechanisms involving well both inflammation.

Язык: Английский

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Causes, Diagnosis, Treatment, and Prognosis of Cardiac Fibrosis: A Systematic Review

Cureus, Год журнала: 2025, Номер unknown

Опубликована: Март 27, 2025

Cardiac fibrosis, characterized by excessive extracellular matrix deposition, contributes to heart failure, arrhythmias, and myocardial dysfunction. Despite advances in understanding its mechanisms, targeted antifibrotic therapies remain limited. This review examines the causes, molecular diagnostic approaches, therapeutic strategies for cardiac fibrosis. A systematic of peer-reviewed studies was conducted, focusing on etiology, diagnosis, treatment, prognosis fibrosis with no specific timeframe. The condition is driven fibroblast activation, inflammatory pathways, mechanical stress, key contributing factors including ischemic disease, hypertension, diabetes, aging. Diagnostic tools such as magnetic resonance imaging T1 mapping biomarkers play a crucial role, natriuretic peptides offering both prognostic value. Galectin-3 has also shown promise marker. Current therapies, RAAS inhibitors beta-blockers, help prevent progression but do not reverse established Emerging plant-based compounds, gene therapy, fibroblast-targeting vaccines, stem cell reprogramming show potential preclinical studies. However, remains major driver disease progression, existing treatments Major gaps include lack validated agents challenges translating findings into clinical applications. Further research essential develop effective interventions.

Язык: Английский

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NOX4-driven Mitochondrial Oxidative Stress in Aging Promotes Myocardial Remodeling and Increases Susceptibility to Ventricular Tachyarrhythmia

Free Radical Biology and Medicine, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

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The Macrophage–Fibroblast Dipole in the Context of Cardiac Repair and Fibrosis

Biomolecules, Год журнала: 2024, Номер 14(11), С. 1403 - 1403

Опубликована: Ноя. 4, 2024

Stromal and immune cells their interactions have gained the attention of cardiology researchers clinicians in recent years as contribution cardiac repair is increasingly recognized. The process heart a particularly critical constellation complex molecular cellular events that characteristically fail to ensure adequate recovery following injury, insult, or exposure stress conditions this regeneration-hostile organ. tremendous consequence pronounced inability maintain homeostatic states being translated numerous ways promoting progress into failure, deadly, irreversible condition requiring organ transplantation. Fibrosis fact response eventually dysfunction fibroblasts are major players process, overproducing collagens other extracellular matrix components when activated. On hand, macrophages may differentially affect depending on status subsets. opposite interaction also probable. We discuss here multifaceted aspects crosstalk cell dipole opportunities it offer for beneficial manipulation approaches will hopefully lead disease interventions.

Язык: Английский

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Bestrahlung des Herzens zur Verbesserung der linksventrikulären Funktion

Strahlentherapie und Onkologie, Год журнала: 2024, Номер 200(9), С. 847 - 849

Опубликована: Июль 17, 2024

Hintergrund Herzinsuffizienz als gemeinsame Endstrecke einer Vielzahl kardialer bzw.kardiovaskulärer Erkrankungen ist mit vielen Millionen Betroffenen weltweit eine Volkskrankheit hohen Mortalität und gravierenden sozioökonomischen Folgen

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