研究证实1-磷酸鞘氨醇受体2（S1PR2）在心血管系统中起重要作用。本课题组新近发现：心梗后心脏中S1PR2表达上调，S1PR2抑制剂减少心梗后心肌细胞凋亡和促进血管新生，提高心梗后心功能；体外实验证实S1PR2抑制剂上调心肌细胞的HIF-1alpha和内皮细胞的eNOS表达。研究已明确HIF-1alpha和eNOS通路在心梗后细胞凋亡和血管新生中起关键作用，据此提出，心肌细胞和内皮细胞的S1PR2分别通过HIF-1alpha和eNOS信号通路调控心梗后细胞凋亡和血管新生。拟利用心肌细胞和血管内皮细胞条件性S1PR2基因敲除小鼠，采用免疫组化和心超在心梗模型上研究心梗后心室重构，结合体外细胞实验和信号通路实验，阐明心肌细胞和血管内皮细胞S1PR2通过调控HIF-1alpha和eNOS信号通路影响心梗后细胞凋亡和血管新生，探索S1PR2抑制剂改善心室重构的有效方法，为防治心衰提供实验依据。

Acute myocardial infarction (MI) is a major public health problem in the 21st century. Pathological cardiac remodeling contributes to the progression of heart failure. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite and plays an important role in cardiovascular function via its receptors, including S1PR1-5. Our previous data showed that the expression of S1PR2 significantly was up-regulated in the heart tissue after MI and that S1PR2 antagonist treatment enhanced post-MI cell survival and angiogenesis, and therefore improved cardiac function, suggesting that S1PR2 plays an essential role in post-MI cardiac remodeling. Our further in vitro data showed that inhibition of S1PR2 elevated HIF-1alpha expression levels in cardiomyocyte cell line H9C2 and eNOS expression in endothelial cell line HUVEC. It is well known that HIF-1alpha and eNOS pathways tightly regulate post-MI cell survival and angiogenesis. Hence, we hypothesize that S1PR2 signaling in cardiomyocytes and vascular endothelial cells controls post-MI cardiac remodeling via HIF-1alpha and eNOS pathway, respectively. To clarify this, we will generate cardiomyocyte specific conditional S1PR2 knock-out mice and vascular endothelial cell specific S1PR2 knock-out mice, and perform MI operation on these mice. We will apply histological analyses and cardiovascular ultrasound to examine the role of S1PR2 in cardiac angiogenesis, cell survival and cardiac function after MI. Meanwhile, we will undertake in vitro experiment to investigate whether S1PR2 controls cardiomyocyte apoptosis and angiogenesis via HIF-1alpha and eNOS signaling pathway. Furthermore, we will treat MI mice with S1PR2 antagonist and optimize the best treatment way to improve post-MI cardiac remodeling. Taken together, this project will reveal unknown functions of S1PR2 in post-MI cardiac remodeling, and uncover novel mechanism how S1PR2 controls cell survival and angiogenesis following MI. Most importantly, this project will raise a new and promising therapeutic option for post-MI heart failure treatment.