流行病学显示心脏微血管损伤是糖尿病心脏病预后关键事件。我们已证明糖尿病大鼠12周时，S1PR1/3通过PKCβⅡ调控细胞凋亡，导致心脏微血管损伤(PLoS ONE.2012)。但后续实验提示糖尿病16周后，心脏细胞凋亡未显著进展，心功能仍持续下降，提示糖尿病心脏病后期存在凋亡以外的其他调控因素。文献提示细胞老化可能是心脏损伤的重要原因。而我们细胞预实验发现，高糖环境下心脏微血管内皮细胞传至第五代后，凋亡变化亦不明显（与动物实验一致），但细胞老化持续加剧，并伴RSK4表达增加，提示RSK4、细胞老化及糖尿病心脏病三者密切相关。而S1PR1/3激动剂FTY720可抑制上述现象，结合文献报道S1PR1/3下游信号与RSK4多有交叉， 进一步坚定本研究假说，即：S1PR1/3通过RSK4调控细胞老化，进而影响糖尿病后期心脏微血管病变及心功能。本研究将为糖尿病心脏病后期防治新靶点的探索提供理论基础。

Epidemiology showed the cardiac microvascular injury is a key factor of prognosis for diabetic ischemic heart disease, which is characterized as cellular apoptosis regulated by S1PR1/3-PKCβⅡdependent pathway ( PLoS ONE. 2012). However, our follow-up research found that after 16 weeks, the cardiac function of diabetic rats continued to decline without obvious progress of apoptosis, which indicated.the presence of other factors regulating the disease. And our cellular preliminary experiment demonstrated that after subcultured to 5th generation under high glucose medium, the cardiac microvascular endothelial cell apoptosis also changed little while senescence kept intensified tendency accompanied with increased RSK4 expression. These all suggested there may be a closed relationship among RSK4, senescence and diabetic heart disease. In addition, the phenomena above could be inhibited by S1PR1/3 agonist FTY720, which suggested the relationship between S1PR1/3 and RSK4 as well as the clues in literature. In brief, all evidences implicit that S1PR1/3 medicate cellular senescence through RSK4, which make great contributions to cardiac microvascular injury and cardiac function in the later stage of diabetic heart disease. Our research will be helpful to provide a theoretical basis for the treatment on diabetic heart disease.