为了明确Bmi-1缺失是否通过激活p16-pRb信号通路，增加氧化应激和上调DNA损伤反应，引起心血管衰老，从而导致心血管功能障碍，我们将给予Bmi-1缺失小鼠补充抗氧化剂N-乙酰半胱氨酸(NAC)或吡咯喹啉醌(PQQ)，并建立Bmi-1和p16或Chk2双基因敲除小鼠模型，利用组织病理学、细胞生物学和分子生物学的方法比较分析上述各组动物的心血管表型差异，包括生存期，细胞增殖、凋亡和衰老，促炎及促纤维化反应，心血管功能，氧化应激和DNA损伤反应，心血管风险因子表达及调控；同时，为了明确Bmi-1缺失引起的血管衰老是否为直接作用，将Bmi-1缺失小鼠的颈总和肠系膜动脉移植到免疫缺陷小鼠皮下，观察微环境改变对Bmi-1缺失引起血管衰老表型的影响。本研究将阐明Bmi-1在防止心血管衰老、维持心血管功能中的作用机制，为临床防治心血管衰老相关疾病提供新的靶标和实验依据。

To determine whether Bmi-1 deficiency resulted in cardiovascular aging by activating p16-Rb signalling pathway, increasing oxidative stress and up-regulating DNA damage response, subsequently inducing cardiovascular dysfunction, Bmi-1 deficiency mice will be fed a dietary antioxidant N-acetyl-cysteine(NAC) or pyrroloquinoline quinone(PQQ) and double Bmi-1 and p16 or Chk2 mutant mouse models will be generated. Cardiovascular phenotypes will be analyzed and compared each other using histopathological, cellular and molecular techniques, including life span, cell proliferation, apoptosis and aging, proinflammation and profibrosis, cardiovascular function, oxidative stress and DNA damage response, and the expression and regulation of cardiovascular risk factors. Moreover, to determine whether vascular aging caused by Bmi-1 deficiency was direct action, mesenteric artery and common carotid artery of Bmi-1 deficiency mice will be transplanted subcutaneously into immunodeficient mice for observing the effect of microenviromental changes to the phenotype of vascular aging caused by Bmi-1 deficiency. This study will elucidate mechanisms of role of Bmi-1 in preventing cardiovascular aging and maintaining cardiovascular function, thus will provide a novel target and experimental basis for the clinic prevention and treatment of cardiovascular aging associated diseases.