MicroRNA-34a Induces Vascular Smooth Muscle Cells Senescence by SIRT1 Downregulation and Promotes the Expression of Age-Associated Pro-inflammatory Secretory Factors

Ileana Badi, Ilaria Burba, Clarissa Ruggeri, Filippo Zeni, Matteo Bertolotti, Alessandro Scopece, Giulio Pompilio, Angela Raucci

Research output: Contribution to journalArticle

Abstract

Arterial aging is a major risk factor for the occurrence of cardiovascular diseases. The aged artery is characterized by endothelial dysfunction and vascular smooth muscle cells altered physiology together with low-grade chronic inflammation. MicroRNA-34a (miR-34a) has been recently implicated in cardiac, endothelial, and endothelial progenitor cell senescence; however, its contribution to aging-associated vascular smooth muscle cells phenotype has not been explored so far. We found that miR-34a was highly expressed in aortas isolated from old mice. Moreover, its well-known target, the longevity-associated protein SIRT1, was significantly downregulated during aging in both endothelial cells and vascular smooth muscle cells. Increased miR-34a as well as decreased SIRT1 expression was also observed in replicative-senescent human aortic smooth muscle cells. miR-34a overexpression in proliferative human aortic smooth muscle cells caused cell cycle arrest along with enhanced p21 protein levels and evidence of cell senescence. Furthermore, miR-34a ectopic expression induced pro-inflammatory senescence-associated secretory phenotype molecules. Finally, SIRT1 protein significantly decreased upon miR-34a overexpression and restoration of its levels rescued miR-34a-dependent human aortic smooth muscle cells senescence, but not senescence-associated secretory phenotype factors upregulation. Taken together, our findings suggest that aging-associated increase of miR-34a expression levels, by promoting vascular smooth muscle cells senescence and inflammation through SIRT1 downregulation and senescence-associated secretory phenotype factors induction, respectively, may lead to arterial dysfunctions.

Original languageEnglish
Pages (from-to)1304-1311
Number of pages8
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume70
Issue number11
DOIs
Publication statusPublished - Nov 1 2015

Keywords

  • Inflammation
  • MiR-34a
  • SASP
  • SIRT1
  • Vascular aging

ASJC Scopus subject areas

  • Ageing
  • Geriatrics and Gerontology
  • Medicine(all)

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