The FGF13‐Caveolin‐1 Axis: A Key Player in the Pathogenesis of Doxorubicin‐ and D‐Galactose‐Induced Premature Cardiac Aging

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Abstract Delaying senescence of cardiomyocytes has garnered widespread attention as a potential target for preventing cardiovascular diseases (CVDs). FGF13 (Fibroblast growth factor 13) been implicated in various pathophysiological processes. However, its role premature myocardial aging and cardiomyocyte remains unknown. Adeno‐associated virus 9 (AAV9) vectors expressing cardiac‐specific Fgf13 knockout (Fgf13KO) mice are utilized to reveal that overexpression deficiency exacerbated alleviated Doxorubicin/D‐galactose‐induced characteristics functional impairment, respectively. Transcriptomics employed identify an association between Caveolin‐1 (Cav1). Mechanistic studies indicated regulated the Cav1 promoter activity expression through p38/MAPK pathway nuclear translocation p65, well binding level PTRF mediate senescence. Furthermore, murine hearts reversed alleviatory effects on phenotype dysfunction. This study demonstrated Cav1‐p53‐p21 axis augment thereby cardiac suggests knockdown may be promising approach combat CVDs response chemotoxicity.

Language: Английский

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Cellular Senescence in Cardiovascular Diseases: From Pathogenesis to Therapeutic Challenges

Journal of Cardiovascular Development and Disease, Journal Year: 2023, Volume and Issue: 10(10), P. 439 - 439

Published: Oct. 23, 2023

Cellular senescence (CS), classically considered a stable cell cycle withdrawal, is hallmarked by progressive decrease in growth, differentiation, and biological activities. Senescent cells (SNCs) display complicated senescence-associated secretory phenotype (SASP), encompassing variety of pro-inflammatory factors that exert influence on the biology both surrounding tissue. Among global mortality causes, cardiovascular diseases (CVDs) stand out, significantly impacting living quality functional abilities patients. Recent data suggest accumulation SNCs aged or diseased systems, suggesting their potential role impairing function. CS operates as double-edged sword: while it can stimulate restoration organs under physiological conditions, also participate organ tissue dysfunction pave way for multiple chronic pathological states. This review explores mechanisms underlie delves into distinctive features characterize SNCs. Furthermore, we describe involvement progression CVDs. Finally, study provides summary emerging interventions either promote suppress discusses therapeutic

Language: Английский

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Higher matrix stiffness promotes VSMC senescence by affecting mitochondria–ER contact sites and mitochondria/ER dysfunction

The FASEB Journal, Journal Year: 2023, Volume and Issue: 37(12)

Published: Nov. 23, 2023

Abstract Abdominal aortic aneurysm (AAA) is a prevalent condition characterized by the weakening and bulging of abdominal aorta. This study aimed to investigate impact stiff matrix on vascular smooth muscle cells (VSMCs) in AAA development. Bioinformatics analysis revealed that differentially expressed genes (DEGs) VSMCs an mouse model were enriched cellular senescence related pathways. To simulate aging‐related changes, cultured matrices, compared those soft matrices exhibited senescence. Furthermore, mutual distance between mitochondria endoplasmic reticulum (ER) was increased, indicating altered mitochondria–endoplasmic contacts (MERCs). The observed upregulation reactive oxygen species (ROS) levels, antioxidant gene expression, decreased mitochondrial membrane potential suggested presence dysfunction matrix. Additionally, induction ER stress‐related indicated dysfunction. These findings collectively impaired functionality both Moreover, our data high lipid levels exacerbated effects stiffness senescence, MERC sites, mitochondria/ER Importantly, treatment with antilipemic agent CI‐981 effectively reversed these detrimental effects. provide insights into role stiffness, dysfunction, stress, metabolism development, suggesting therapeutic targets for intervention.

Language: Английский

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Multifaceted roles of Meg3 in cellular senescence and atherosclerosis

Atherosclerosis, Journal Year: 2024, Volume and Issue: 392, P. 117506 - 117506

Published: March 8, 2024

Background and aims Long noncoding RNAs are involved in the pathogenesis of atherosclerosis. As long maternally expressed gene 3 (Meg3) prevents cellular senescence hepatic vascular endothelium obesity-induced insulin resistance, we decided to examine its role Methods results By analyzing our data human mouse from Gene Expression Omnibus database, found that Meg3 expression was reduced humans mice with cardiovascular disease, indicating potential In Ldlr−/− fed on a Western diet for 12 weeks, silencing by chemically modified antisense oligonucleotides attenuates formation atherosclerotic lesions 34.9% 20.1% male female mice, respectively, revealed en-face Oil Red O staining, which did not correlate changes plasma lipid profiles. Real-time quantitative PCR analysis markers p21 p16 deficiency aggravates but at aortic roots. Human transgenic were generated gain-of-function development atherosclerosis induced PCSK9 overexpression. overexpression promotes lesion 29.2% knock-in independent effects inhibits senescence, while it likely impairing mitochondrial function delaying cell cycle progression. Conclusions Our demonstrate addition, regulates tissue-specific manner during Thus, demonstrated has multifaceted roles

Language: Английский

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Inhibitory immune checkpoints suppress the surveillance of senescent cells promoting their accumulation with aging and in age-related diseases

Biogerontology, Journal Year: 2024, Volume and Issue: 25(5), P. 749 - 773

Published: July 1, 2024

Abstract The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark the aging process and many age-related diseases. This modification has been called senescence-associated secretory phenotype (SASP) observed in cultured isolated from aged tissues. Currently, there debate whether should be attributed to increased generation or defect their elimination Emerging studies have revealed that display an expression several inhibitory immune checkpoint ligands, especially those programmed cell death protein-1 (PD-1) ligand-1 (PD-L1) proteins. It known PD-L1 cancer cells, target PD-1 receptor cytotoxic CD8 + T natural killer (NK) disturbing functions, e.g., evoking decline activity promoting exhaustion even apoptosis. An increase level protein was able suppress surveillance inhibit by NK cells. Senescent are express ligands for receptors, i.e., PD-1, LILRB4, NKG2A, TIM-3, SIRPα receptors. Here, I will briefly describe pathways examine these checkpoints could involved evasion with seems plausible enhanced signaling can prevent thus promote process.

Language: Английский

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