Antagonism of miR-148a attenuates atherosclerosis progression in APOBTGApobec-/-Ldlr+/- mice: A brief report

Noemi Rotllan, Xinbo Zhang, Alberto Canfrán-Duque, Leigh Goedeke, Raquel Griñán, Cristina M. Ramírez, Yajaira Suárez, Carlos Fernández-Hernando

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Objective: miR-148a-3p (miR-148a) is a hepatic and immune-enriched microRNA (miRNA) that regulates macrophage-related lipoprotein metabolism, cholesterol homeostasis, and inflammation. The contribution of miR-148a-3p to the progression of atherosclerosis is unknown. In this study, we determined whether miR-148a silencing mitigated atherogenesis in APOBTGApobec-/-Ldlr+/- mice. Methods: APOBTGApobec-/-Ldlr+/- mice were fed a typical Western-style diet for 22 weeks and injected with a nontargeting locked nucleic acid (LNA; LNA control) or miR-148a LNA (LNA 148a) for the last 10 weeks. At the end of the treatment, the mice were sacrificed, and circulating lipids, hepatic gene expression, and atherosclerotic lesions were analyzed. Results: Examination of atherosclerotic lesions revealed a significant reduction in plaque size, with marked remodeling of the lesions toward a more stable phenotype. Mechanistically, miR-148a levels influenced macrophage cholesterol efflux and the inflammatory response. Suppression of miR-148a in murine primary macrophages decreased mRNA levels of proinflammatory M1-like markers (Nos2, Il6, Cox2, and Tnf) and increased the expression of anti-inflammatory genes (Arg1, Retlna, and Mrc1). Conclusions: Therapeutic silencing of miR148a mitigated the progression of atherosclerosis and promoted plaque stability. The antiatherogenic effect of miR-148a antisense therapy is likely mediated by the anti-inflammatory effects observed in macrophages treated with miR-148 LNA and independent of significant changes in circulating low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C).

Original languageEnglish
Article number113419
JournalBiomedicine and Pharmacotherapy
Volume153
DOIs
StatePublished - Sep 2022
Externally publishedYes

Keywords

  • Atherosclerosis progression
  • Cholesterol Efflux
  • M2-like phenotype
  • MiR-148a
  • Plaque stability
  • Therapeutic inhibition

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