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Deciphering m 6 A methylation in monocyte-mediated cardiac fibrosis and monocyte-hitchhiked erythrocyte microvesicle biohybrid therapy.
- Source :
-
Theranostics [Theranostics] 2024 Jun 01; Vol. 14 (9), pp. 3486-3508. Date of Electronic Publication: 2024 Jun 01 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- Rationale: Device implantation frequently triggers cardiac remodeling and fibrosis, with monocyte-driven inflammatory responses precipitating arrhythmias. This study investigates the role of m <superscript>6</superscript> A modification enzymes METTL3 and METTL14 in these responses and explores a novel therapeutic strategy targeting these modifications to mitigate cardiac remodeling and fibrosis. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from patients with ventricular septal defects (VSD) who developed conduction blocks post-occluder implantation. The expression of METTL3 and METTL14 in PBMCs was measured. METTL3 and METTL14 deficiencies were induced to evaluate their effect on angiotensin II (Ang II)-induced myocardial inflammation and fibrosis. m <superscript>6</superscript> A modifications were analyzed using methylated RNA immunoprecipitation followed by quantitative PCR. NF-κB pathway activity and levels of monocyte migration and fibrogenesis markers (CXCR2 and TGF-β1) were assessed. An erythrocyte microvesicle-based nanomedicine delivery system was developed to target activated monocytes, utilizing the METTL3 inhibitor STM2457. Cardiac function was evaluated via echocardiography. Results: Significant upregulation of METTL3 and METTL14 was observed in PBMCs from patients with VSD occluder implantation-associated persistent conduction block. Deficiencies in METTL3 and METTL14 significantly reduced Ang II-induced myocardial inflammation and fibrosis by decreasing m <superscript>6</superscript> A modification on MyD88 and TGF-β1 mRNAs. This disruption reduced NF-κB pathway activation, lowered CXCR2 and TGF-β1 levels, attenuated monocyte migration and fibrogenesis, and alleviated cardiac remodeling. The erythrocyte microvesicle-based nanomedicine delivery system effectively targeted inflamed cardiac tissue, reducing inflammation and fibrosis and improving cardiac function. Conclusion: Inhibiting METTL3 and METTL14 in monocytes disrupts the NF-κB feedback loop, decreases monocyte migration and fibrogenesis, and improves cardiac function. Targeting m <superscript>6</superscript> A modifications of monocytes with STM2457, delivered via erythrocyte microvesicles, reduces inflammation and fibrosis, offering a promising therapeutic strategy for cardiac remodeling associated with device implantation.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.<br /> (© The author(s).)
- Subjects :
- Humans
Male
Animals
Erythrocytes metabolism
Adenosine analogs & derivatives
Adenosine metabolism
Female
Methylation
Mice
Transforming Growth Factor beta1 metabolism
Cell-Derived Microparticles metabolism
Leukocytes, Mononuclear metabolism
Angiotensin II metabolism
Receptors, Interleukin-8B metabolism
Receptors, Interleukin-8B genetics
Ventricular Remodeling
Myocardium metabolism
Myocardium pathology
Nanomedicine methods
Methyltransferases metabolism
Methyltransferases genetics
Monocytes metabolism
Fibrosis
NF-kappa B metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1838-7640
- Volume :
- 14
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Theranostics
- Publication Type :
- Academic Journal
- Accession number :
- 38948064
- Full Text :
- https://doi.org/10.7150/thno.95664