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FTY720 Protects Cardiac Microvessels of Diabetes: A Critical Role of S1P1/3 in Diabetic Heart Disease 1. 2. 3 1 1 1 1 Zhiyong Yin , Linni Fan , Liping Wei , Haokao Gao , Rongqing Zhang , Ling Tao , Feng Cao , Haichang Wang1* 1 Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi’an City, Shaanxi Province, China, 2 Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi’an City, Shaanxi Province, China, 3 Department of Cardiology, Tianjin Union Medicine Center, Tianjin, China Abstract Background: Diabetes is associated with an increased risk of cardiac microvascular disease. The mechanisms by which this damage occurs are unknown. However, research suggests that signaling through the sphingosine-1-phosphates receptor 1 and 3 (S1P1/3) by FTY720, a sphiongolipid drug that is structually similar to SIP, may play a role in the treatment on cardiac microvascular dysfunction in diabetes. We hypothesized that FTY720 might exert the cardioprotective effects of S1P1 and S1P3 viaprotein kinase C-beta (PKCb II) signaling pathway. Methodology/Principal Findings: Transthoracic echocardiography was performed to detect the change of cardiac function. Scanning and transmission electron microscope with lanthanum tracer were used to determine microvascular ultrastructure and permeability in vivo. Apoptosis was detected by TUNEL and CD31 dual labeling in paraffin-embedded sections. Laser capture miscrodissection was used to assess cardiac micovascular endothelial cells (CMECs) in vivo. RT-PCR and Western blot analysis were used to determine the mRNA levels and protein expression of S1P1, S1P3, and PKCb II. In the diabetic rats vs. controls, cardiac capillaries showed significantly higher density