title: MicroRNA-34a Induces Vascular Smooth Muscle Cells Senescence by SIRT1 Downregulation and Promotes the Expression of Age-Associated Pro-inflammatory Secretory Factors.
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.
authors.affiliation: Unit of Vascular Biology and Regenerative Medicine and Unit of Cardiovascular Regeneration and Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Ileana
authors.initials: I
authors.lastname: Badi
authors.affiliation: Unit of Vascular Biology and Regenerative Medicine and.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Burba
authors.affiliation: Unit of Vascular Biology and Regenerative Medicine and Unit of Cardiovascular Regeneration and Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Ruggeri
authors.affiliation: Unit of Vascular Biology and Regenerative Medicine and Unit of Cardiovascular Regeneration and Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Zeni
authors.affiliation: Unit of Vascular Biology and Regenerative Medicine and Unit of Cardiovascular Regeneration and Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bertolotti
authors.affiliation: Unit of Vascular Biology and Regenerative Medicine and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Scopece
authors.affiliation: Unit of Vascular Biology and Regenerative Medicine and.
authors.forename: Giulio
authors.initials: G
authors.lastname: Pompilio
authors.affiliation: Unit of Vascular Biology and Regenerative Medicine and Unit of Cardiovascular Regeneration and Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy. araucci@ccfm.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Raucci
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D018929:Cell Culture Techniques; D016922:Cellular Senescence / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C522425:MIRN34 microRNA, human; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Inflammation.; MiR-34a; SASP; SIRT1; Vascular aging