二肽基肽酶III在小鼠心肌细胞中的生理学功能及在缺血再灌注损伤中的作用

Oxidative stress response, associated with oxygen free radical, is the main mechanism of myocardial ischemia-reperfusion injury (I/RI). It is indicated that dipeptidyl peptidase III (DPPIII) involves various physiological and pathological processes in cancer, including oxidative stress response. However, the physiological or pathological functions of DPP in cardiovascular system have not been elucidated yet. Our previous data firstly indicated that, DPP III is highly expressed in cardiomyocytes and vascular smooth muscle cells, and shows its protective role on hypertensive heart.Thus, the protective role of DPP III in cardiomyocytes under I/RI through inhibiting oxidative stress was hypothesized. The mouse heart and primary culture of cardiomyocytes under I/RI, as well as HL-1 cells, will be employed to observe and investigate the protectively physiological and pathological effects of DPP III in cardiomyocytes and knock out (KO) mouse against oxidative stress, and explore the potential mechnism in vivo and vitro though various molecular biology techniques, such as flow cytometry, RT-PCR and so on.

与氧自由基相关的氧化应激反应是心肌缺血再灌注损伤重要机制。研究表明，二肽基肽酶III（Dipeptidyl peptidase III，DPP III）在肿瘤中参与包括氧化应激调控在内的各种生理病理过程，但其在心血管系统的生理病理功能尚属未知。前期，我们首次发现DPPIII在心肌细胞及平滑肌细胞高表达，且对高血压心脏具有保护作用。因此，我们提出“DPP III通过抑制氧化应激反应参与对再灌注损伤心肌细胞的保护作用”这一假说。为证实这一假说，我们利用DPP III KO（Knock out）小鼠心脏和乳鼠心肌细胞原代培养及HL-1细胞，通过复制缺血再灌注损伤模型，采用流式细胞仪、RT-PCR等分子生物学技术，从体内外两个水平，观察和评价DPP III在心肌细胞中的生理作用，以及探讨其通过抗氧化应激发挥对缺血再灌注损伤病理过程中心肌细胞的保护作用和机制。

该项目紧密围绕人口老龄化相关疾病，着重探讨冠心病和糖尿病的靶器官保护，课题旨在评价 DPP III 参与下的心血管系统的生理功能，并探讨在心肌缺血再灌注损伤中的相应的分子机制，为心肌缺血/再灌注损伤的防治提供理论基础以及新的思路和靶点。其中包括：证实小鼠心肌组织存在 DPP III 表达；DPP III对糖尿病db/db小鼠的心脏、肾脏具有保护作用，具体表现在减少尿蛋白、延缓足细胞损害、心肌纤维化程度降低等，该部分成果已撰写文章并投稿。研究成果提示其有望成为保护心肾靶器官的药物，具有基础研究和临床转化价值，具有领先性。. 此外，项目执行期间对于高尿酸血症相关的研究也增加了临床医生对高尿酸血症的认识，这对后续开展早期高危人群筛查具有临床价值。