Genetic Depletion of T cell S1P Receptor 1 Exhibits Improved Cardiac Function and Less Fibrosis in Streptozotocin‐Induced Type 1 Diabetic Mice

Abstract

IntroductionT lymphocyte infiltration into myocardium has been observed in patients with diabetes. Sphingosine 1‐phosphate 1 (S1P1) regulates mature T cells egress from lymphoid organ to blood and peripheral organs. The role of T lymphocytes in diabetic hearts remained elusive. Methods and Results: Depletion of T cell S1P1 receptors was attained by breeding of S1P1loxP/loxP mice with Lck‐driven Cre transgenic mice. T cell‐specific S1P1 receptor knock‐out mice (TCS1P1KO) and littlemate wild‐type mice (WT) were divided into vehicle control and streptozotocin (STZ) groups. Type 1 diabetes was induced by five days injection (i.p.) of STZ at a dose of 50 mg/kg. Control mice were injected buffer only. Body weight and fasting blood glucose level was measured at the beginning, 4, and 11 weeks. Mature CD4 and CD8 T cells in blood as well as regulatory T cells (Tregs) and Th17 cell in both spleen and blood were counted by flow cytometry. Masson's Trichrome staining was conducted to assess fibrosis. Cardiac contractile force was measured by Langendorff perfusion at the end of 11 weeks. TCS1P1KO mice had reduced CD4 T cells (1.15+/‐0.30% vs 25.06+/‐0.64% in WT, P<0.01, n=4‐5 per group) and CD8 T cells (2.09+/‐042% vs 14.72+/‐038% in WT, P<0.01) in blood. Treg cells increased in blood in WT STZ mice (1.75+/‐0.20% vs 0.39+/‐0.18% in KO STZ mice). TCS1P1KO STZ mice exhibited less cardiac fibrosis and enhanced cardiac contractile force compared to WT STZ mice.ConclusionSelective depletion of T cell S1P1 reduces mature T lymphocytes in circulation and exerts improved cardiac function and less myocardial fibrosis in diabetic hearts.