Abstract
The senescence of vascular smooth muscle cells (VSMCs), characterized by the acquisition of senescence-associated secretory phenotype (SASP), is relevant for VSMCs osteoblastic differentiation and vascular calcification (VC). MicroRNA-34a (miR-34a) is a driver of such phenomena and could play a role in vascular inflammaging. Herein, we analyzed the relationship between miR-34a and the prototypical SASP component IL6 in in vitro and in vivo models. miR-34a and IL6 levels increased and positively correlated in aortas of 21 months-old male C57BL/6J mice and in human aortic smooth muscle cells (HASMCs) isolated from donors of different age and undergone senescence. Lentiviral overexpression of miR-34a in HASMCs enhanced IL6 secretion. HASMCs senescence and calcification accelerated after exposure to conditioned medium of miR-34a-overexpressing cells. Analysis of miR-34a-induced secretome revealed enhancement of several pro-inflammatory cytokines and chemokines, including IL6, pro-senescent growth factors and matrix-degrading molecules. Moreover, induction of aortas medial calcification and concomitant IL6 expression, with an overdose of vitamin D, was reduced in male C57BL/6J Mir34a−/− mice. Finally, a positive correlation was observed between circulating miR-34a and IL6 in healthy subjects of 20-90 years. Hence, the vascular age-associated miR-34a promotes VSMCs SASP activation and contributes to arterial inflammation and dysfunctions such as VC.
Highlights
The deterioration of arterial anatomy and physiology that occurs during chronological aging is a risk factor for cardiovascular morbidity and all-cause mortality [1]
Senescent vascular smooth muscle cells (VSMCs) express bone-related genes, like Runt-related transcription factor 2 (Runx2), alkaline phosphatase and osteocalcin that favor their maladaptive switching to an osteoblastic phenotype and eventually, the onset of vascular calcification (VC), a cardiovascular complication characterized by hydroxyapatite crystals deposition and mineralization of the arterial wall [13,14,15]
Arterial inflammaging is a driver of VC as well since many senescence-associated secretory phenotype (SASP) molecules such as Interleukin 6 (IL6), bone morphogenetic protein 2 (BMP2) and osteoprotegerin (OPG) are known to reinforce osteoblastic transition of nearby senescent VSMCs [16,20]
Summary
The deterioration of arterial anatomy and physiology that occurs during chronological aging is a risk factor for cardiovascular morbidity and all-cause mortality [1]. Aged arteries are characterized by functional changes of vascular smooth muscle cells (VSMCs) from a contractile and quiescent status to a senescent phenotype distinguishable for an enlarged morphology, loss of contraction, irreversible growth arrest, increased activity of senescence-associated β-galactosidase (SA-β-gal) and enhanced expression the cyclin-dependent kinase inhibitors p21 and p16 and the tumor suppressor gene p53 [2,3,4,5]. Senescent VSMCs express bone-related genes, like Runt-related transcription factor 2 (Runx2), alkaline phosphatase and osteocalcin that favor their maladaptive switching to an osteoblastic phenotype and eventually, the onset of vascular calcification (VC), a cardiovascular complication characterized by hydroxyapatite crystals deposition and mineralization of the arterial wall [13,14,15]. MiR-34a could represent a promising target to develop a beneficial strategy to favor healthy lifespan
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