长期摄入糖替代品加重小鼠脑缺血损伤的血管新生机制研究

In our current food supply, sugar substitutes are widely used in beverages and other food products. Recently, accumulating evidences suggest that dietary consumption of these compounds may also increase the risk of metabolic disorder, which is one of major risk factors for cerebrocardiovascular diseases such as stroke. Our previous studies demonstrated that Long-term consumption of sugar substitutes aggravated cerebral ischemic injury in mice. The angiogenesis play an important role in recovery after an ischemic stroke. Accordingly, we hypothesize that Long-term consumption of sugar substitutes aggravated cerebral ischemic injury via impairing angiogenesis in ischemic brain in mice. To test this hypothesis, this project will perform following 2 aims: 1) to determine the relationship between the aggravated cerebral ischemic injury produced by sugar substitutes and the impairment of angiogenesis in ischemic brain; 2) to investigate the mechanisms underlying the impairment of angiogenesis in ischemic brain produced by chronic consumption of sugar substitutes. Stroke is a devastating disease and the major cause of mortality and morbidity worldwide, and the prevention and treatment of stroke is still a global problem to date. Therefore, this project may provide a new prevention and therapeutic strategy for ischemic stroke.

为了避免过多摄入糖对人体健康造成不良影响，糖替代品（如人工甜味剂、糖醇等）被广泛应用于饮料和食品中。但近期有研究表明，长期摄入这些糖替代品也可能导致机体代谢功能异常。我们的前期工作首次发现，长期摄入糖替代品（美国FDA批准用于饮料和食品的剂量）可加重小鼠脑缺血损伤。鉴于脑缺血损伤的严重程度与血管新生功能密切相关，我们推测：长期摄入糖替代品可通过降低小鼠的血管新生功能，从而加重其脑缺血损伤。本项目拟通过下列实验来验证该假设：确定长期摄入糖替代品加重小鼠脑缺血损伤与其降低血管新生功能的关系;阐明长期摄入糖替代品降低小鼠血管新生功能的机制。目前，中国心脑血管病死亡占城乡居民总死亡原因的首位，已成为重大的公共卫生问题，而各类糖替代品在日常生活中可通过饮料和食品被被广泛摄入体内。所以，本项目研究长期摄入糖替代品加重小鼠脑缺血损伤的机制，有可能为心脑血管病的预防和治疗提供新的思路。

为了避免过多摄入糖对人体健康造成不良影响，糖替代品（如人工甜味剂、糖醇等）被广泛应用于饮料和食品中。但近期有研究表明，长期摄入这些糖替代品也可能导致机体代谢功能异常。我们的研究证实，1）与对照小鼠比较，长期摄入糖替代品小鼠的内皮祖细胞（EPC）功能受损、脑缺血区血管新生能力显著降低、脑缺血损伤明显加重。提示，糖替代品加重小鼠脑缺血损伤可能与其损伤EPC功能、降低血管新生能力有关。2）长期摄入糖替代品在损伤小鼠EPC功能的同时，可显著降低小鼠EPC对脑缺血区血管新生、脑缺血损伤的改善作用。提示，糖替代品可损伤小鼠EPC对脑缺血区血管新生的促进作用和对脑缺血损伤的治疗作用。3）长期摄入糖替代品在损伤小鼠EPC功能的同时，可显著降低小鼠EPC条件培养基对脑缺血损伤的改善作用。提示，糖替代品可损伤小鼠EPC的旁分泌功能。4）长期摄入糖替代品损伤小鼠EPC功能可能与其增高EPC中超氧阴离子水平和降低EPC中NO水平有关，糖替代品的这个作用可能与其下调EPC中的MnSOD、CuZnSOD表达水平和上调Rac1表达水平有关。综上所述，长期摄入糖替代品可损伤小鼠内皮祖细胞介导的血管新生功能，从而加重小鼠的脑缺血损伤。目前，中国心脑血管病死亡占城乡居民总死亡原因的首位，已成为重大的公共卫生问题，而各类糖替代品在日常生活中可通过饮料和食品被被广泛摄入体内。所以，本项目研究长期摄入糖替代品加重小鼠脑缺血损伤的机制，有可能为心脑血管病的预防和治疗提供新的理论参考。