Interleukin 6 reduces vascular smooth muscle cell apoptosis via Prep1 and is associated with aging

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 18 months 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 H2O2‐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.

Resveratrol Improves Endothelial Function by A PREP1-Mediated Pathway in Mouse Aortic Endothelial Cells

“…Actually, whether RSV can regulate PREP1 levels directly or indirectly through the modulation of some PREP1 inducers is not clear. We have shown that Il-6 can increase Prep1 expression in VSMC [21]. In addition, Whung B.S.…”

“…More recently, we have shown how PREP1 increases in the aorta of aged mice and in senescent vascular smooth muscle cells (VSMCs) and is involved in the neointimal formation of reducing VSMCs apoptosis. In particular, PREP1 mediates Il-6-antiapoptotic action on VSMCs through a mechanism involving both p53 and Bcl-xL, and this effect is particularly clear in senescence [21].…”

“…In order to investigate the role of PREP1 in vivo, we performed experiments on aged Prep1 i/+ mice, which expressed low levels of this protein. This animal model is quite interesting because, as described above, it has better insulin sensitivity and reduced neointimal formation [17][18][19]21]. In addition, since PREP1 increases during WT mice aging [21], it is possible to hypothesize the possible role of this transcription factor in agerelated diseases.…”

“…More recently, we have observed that PREP1, by inducing aortic wall thickening, can contribute to vascular dysfunction with advancing age. In particular, an increase in PREP1 has been found in the aorta of aged mice and in senescent vascular smooth muscle cells (VSMCs), which promotes neointimal formation by reducing VSMCs apoptosis [21]. In the present work, we evaluated the role of PREP1 in endothelial function.…”

Studies of effector molecules exerting autonomous and nonautonomous influence of T lymphocyte apoptosis under the conditions of in vitro “cell neighborhood” in healthy people and patients with rheumatoid arthritis

“…Повышение уровня IL-6 в области СА1 гиппокампа приводит к плейотропным защитным действиям, включая снижение оксидативного стресса и модуляцию аутофагии, антивоспалительную активацию и антиапоптотические эффекты [33]. Показано возрастное увеличение IL-6 у стареющих животных, и опосредованное модулированием Bcl-xL и p53 снижение апоптоза [8]. В то же время интерлейкин-6 усиливал TNFα, а TRAIL/ Apo2L индуцировал гибель клеток в различных раковых тканях человека, происходящих от злокачественной глиомы, меланомы, рака молочной железы и лейкемии, хотя эффект не был обнаружен при применении только IL-6.…”