Yoshida Yohko, Hayashi Yuka, Suda Masayoshi, Tateno Kaoru, Okada Sho, Moriya Junji, Yokoyama Masataka, Nojima Aika, Yamashita Masakatsu, Kobayashi Yoshio, Shimizu Ippei, Minamino Tohru
Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
PLoS One. 2014 Jun 20;9(6):e100359. doi: 10.1371/journal.pone.0100359. eCollection 2014.
Evolutionarily conserved Notch signaling controls cell fate determination and differentiation during development, and is also essential for neovascularization in adults. Although recent studies suggest that the Notch pathway is associated with age-related conditions, it remains unclear whether Notch signaling is involved in vascular aging. Here we show that Notch signaling has a crucial role in endothelial cell senescence. Inhibition of Notch signaling in human endothelial cells induced premature senescence via a p16-dependent pathway. Conversely, over-expression of Notch1 or Jagged1 prolonged the replicative lifespan of endothelial cells. Notch1 positively regulated the expression of inhibitor of DNA binding 1 (Id1) and MAP kinase phosphatase 1 (MKP1), while MKP1 further up-regulated Id1 expression by inhibiting p38MAPK-induced protein degradation. Over-expression of Id1 down-regulated p16 expression, thereby inhibiting premature senescence of Notch1-deleted endothelial cells. These findings indicate that Notch1 signaling has a role in the regulation of endothelial cell senescence via a p16-dependent pathway and suggest that activation of Notch1 could be a new therapeutic target for treating age-associated vascular diseases.
进化上保守的Notch信号通路在发育过程中控制细胞命运决定和分化，对成体中的新血管形成也至关重要。尽管最近的研究表明Notch通路与年龄相关疾病有关，但Notch信号是否参与血管衰老仍不清楚。在此我们表明，Notch信号在内皮细胞衰老中起关键作用。抑制人内皮细胞中的Notch信号通过p16依赖性途径诱导过早衰老。相反，Notch1或Jagged1的过表达延长了内皮细胞的复制寿命。Notch1正向调节DNA结合抑制因子1（Id1）和丝裂原活化蛋白激酶磷酸酶1（MKP1）的表达，而MKP1通过抑制p38丝裂原活化蛋白激酶诱导的蛋白质降解进一步上调Id1表达。Id1的过表达下调p16表达，从而抑制Notch1缺失的内皮细胞的过早衰老。这些发现表明，Notch1信号通过p16依赖性途径在调节内皮细胞衰老中起作用，并提示Notch1的激活可能是治疗年龄相关血管疾病的新治疗靶点。
