| First Author | Cimmino I | Year | 2021 |
| Journal | FASEB J | Volume | 35 |
| Issue | 11 | Pages | e21989 |
| PubMed ID | 34679197 | Mgi Jnum | J:323047 |
| Mgi Id | MGI:6844919 | Doi | 10.1096/fj.202100943R |
| Citation | Cimmino I, et al. (2021) Interleukin 6 reduces vascular smooth muscle cell apoptosis via Prep1 and is associated with aging. FASEB J 35(11):e21989 |
| abstractText | Aging exacerbates neointimal formation by reducing apoptosis of vascular smooth muscle cells (VSMCs) and induces inflammation within vascular wall. Prep1 is a homeodomain transcription factor which stimulates the expression of proinflammatory cytokines in aortic endothelial cell models and plays a primary role in the regulation of apoptosis. In this study, we have investigated the role of Prep1 in aorta of Prep1 hypomorphic heterozygous mice (Prep1(i/+) ) and in VSMCs, and its correlation with aging. Histological analysis from Prep1(i/+) aortas revealed a 25% reduction in medial smooth muscle cell density compared to WT animals. This result paralleled higher apoptosis, caspase 3, caspase 9 and p53 levels in Prep1(i/+) mice and lower Bcl-xL. Prep1 overexpression in VSMCs decreased apoptosis by 25% and caspase 3 and caspase 9 expression by 40% and 37%. In parallel, Bcl-xL inhibition by BH3I-1 and p53 induction by etoposide reverted the antiapoptotic effect of Prep1. Experiments performed in aorta from 18 months old WT mice showed a significant increase in Prep1, p16(INK4) , p21(Waf1) and interleukin 6 (IL-6) compared to youngest animals. Similar results have been observed in H2 O2 -induced senescent VSMCs. Interestingly, the synthetic Prep1 inhibitory peptide Prep1 (54-72) reduced the antiapoptotic effects mediated by IL-6, particularly in senescent VSMCs. These results indicate that IL-6-Prep1 signaling reduces apoptosis, by modulating Bcl-xL and p53 both in murine aorta and in VSMCs. In addition, age-dependent increase in IL-6 and Prep1 in senescent VSMCs and in old mice may be involved in the aging-related vascular dysfunction. |
