Induction of let-7d-5p miRNA modulates aortic smooth muscle inflammatory signaling and phenotypic switching.
Atherosclerosis
; 395: 117573, 2024 Aug.
Article
en En
| MEDLINE
| ID: mdl-38796407
ABSTRACT
BACKGROUND AND AIMS:
Activation of vascular smooth muscle cell inflammation is recognised as an important early driver of vascular disease. We have previously identified the let-7 miRNA family as important regulators of inflammation in in vitro and in vivo models of atherosclerosis. Here we investigated a dual statin/let-7d-5p miRNA combination therapy approach to target human aortic SMC (HAoSMC) activation and inflammation.METHODS:
In vitro studies using primary HAoSMCs were performed to investigate the effects of let-7d-5p miRNA overexpression and inhibition. HAoSMCs were treated with combinations of the inflammatory cytokine tumor necrosis factor-α (TNF-α), and atorvastatin or lovastatin. HAoSMC Bulk RNA-seq transcriptomics of HAoSMCs revealed downstream regulatory networks modulated by let-7d-5p miRNA overexpression and statins. Proteome profiler cytokine array, Western blotting and quantitative PCR analyses were performed on HAoSMCs to validate key findings.RESULTS:
Let-7d-5p overexpression significantly attenuated TNF-α-induced upregulation of IL-6, ICAM1, VCAM1, CCL2, CD68, MYOCD gene expression in HAoSMCs (p<0.05). Statins (atorvastatin, lovastatin) significantly attenuated inflammatory gene expression and upregulated Let-7d levels in HAoSMCs (p<0.05). Bulk RNA-seq analysis of a dual Let-7d-5p overexpression/statin therapy in HAoSMCs revealed that let-7d-5p activation and statins converge on key inflammatory pathways (IL-6, IL-1ß, TNF-α, IFN-γ). Let-7d-5p overexpression led to reduced expression of the ox-LDL receptor OLR1, and this was associated with lower ox-LDL uptake in HAoSMCs. In silico analysis of smooth muscle cell phenotypic switching shows that overexpression of let-7d-5p in HAoSMCs maintains a contractile phenotype.CONCLUSIONS:
Targeting the Let-7 network alongside statins can modulate HAoSMC activation and attenuate key inflammatory pathway signals.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Aorta
/
Fenotipo
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Transducción de Señal
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Inhibidores de Hidroximetilglutaril-CoA Reductasas
/
Miocitos del Músculo Liso
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MicroARNs
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Atorvastatina
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Músculo Liso Vascular
Límite:
Humans
Idioma:
En
Revista:
Atherosclerosis
Año:
2024
Tipo del documento:
Article
País de afiliación:
Irlanda
Pais de publicación:
Irlanda