Abstract
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 (Prep1i/+ ) and in VSMCs, and its correlation with aging. Histological analysis from Prep1i/+ 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 Prep1i/+ 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 18months old WT mice showed a significant increase in Prep1, p16INK4 , p21Waf1 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.
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