代谢综合征高游离脂肪酸血症促血管硬化的作用和机制研究

High serum levels of free fatty acid (FFA) plays a curial role in the pathogenesis of cardiovascular events in patients with metabolic syndrome. High FFA levels lead to endothelial dysfunction and arterial stiffness, exacerbating hypertension and subsequent target organ damage. Until now, the mechanism underlying high FFA levels induced vascular remodeling and stiffness remains elusive, even the type of “criminal” FFAs, which cause vascular stiffness, is not clear either. Our recent data confirm that: 1) poly(ADP-ribose) polymerase-1 (PARP-1) activation mediates the neuroendocrine-hormones induced vascular fibrosis and hypertension; 2) many transcriptional factors and signaling proteins exerting important functions in vascular remodeling and fibrosis are regulated by PARP1; 3) PARP1 plays a crucial role in the development of high-fat diet induced elevation of serum FFA levels; 4) PARP1 in endothelial cells and vascular smooth muscle cells can be activated by saturated fatty acid treatment. We thus hypothesize that PARP1 is a key protein in pathogenesis of high fat diet induced high serum levels of FFA and vascular stiffness in patient with metabolic syndrome. In this project, we aim to clarify the role for PARP1 in the pathogenesis of high serum FFA levels induced vascular stiffness, providing a new target and theoretical and experimental basis for the improvement of clinical treatment.

高游离脂肪酸（free fatty acid, FFA）血症是代谢综合征患者心脑血管事件增加的重要原因。目前已知，高FFA血症会导致血管功能受损并发生硬化，从而加重血压增高和靶器官损害，但其具体机制尚不清楚；同时，能引起血管硬化的“有害”FFA种类也不明确。我们证实，1）1型多聚ADP核糖合成酶（PARP1）激活介导了神经内分泌激素所致血管纤维化和血压升高的发生;2）许多在血管重构和纤维化过程中起重要作用的转录因子和信号分子受PARP1调控；3）PARP1在高脂饮食致高FFA血症的发病中起着重要的作用；4）饱和脂肪酸可激活血管内皮和平滑肌细胞内的PARP1。据此，我们推测PARP1是代谢综合症患者高FFA血症致血管硬化的关键蛋白。本项目深入研究并阐明 PARP1在高FFA血症致血管硬化发生发展的作用及机制，所得结果将为临床治疗进步提供新的靶点和理论实验依据。

高游离脂肪酸（free fatty acid, FFA）血症是代谢综合征患者心脑血管事件增加的重要原因。目前已知，高FFA血症会导致血管功能受损并发生硬化，从而加重血压增高和靶器官损害，但其具体机制尚不清楚。 我们的结果证实长期高脂饮食等情况下，肝脏中的PARP1被激活，活化的PARP通过对在脂质代谢过程中起重要作用的PPARα、LXRα和FXR等的作用，抑制相关阻止中TG和FFA的氧化利用，导致机体脂肪负荷增加，循环FFA增加；此后，增高的FFA 通过直接和间接（通过激活RASS 系统、炎症反应等）途径促使血管内皮细胞、平滑肌细胞等血管壁组成细胞内PARP1 激活，其后，活化的PARP1 进而通过改变相关转录因子和信号分子的活性，导致平滑肌细胞增殖迁移并表达大量纤维化相关蛋白等作用，促使血管发生硬化，血压增高。据此，我们得出结论PARP1是代谢综合症患者高FFA血症致血管硬化的关键蛋白，本项目所得结果将为临床治疗进步提供新的靶点和理论实验依据。