title: Depletion of T lymphocytes ameliorates cardiac fibrosis in streptozotocin-induced diabetic cardiomyopathy.
abstract: T cell infiltration has been associated with increased coronary heart disease risk in patients with diabetes mellitus. Effect of modulation of T cell trafficking on diabetes-induced cardiac fibrosis has yet to be determined. Therefore, our aim was to investigate the circulatory T cell depletion-mediated cardioprotection in streptozotocin-induced diabetic cardiomyopathy. Fingolimod (FTY720), an immunomodulatory drug, was tested in wild-type (WT) C57BL/6 and recombination activating gene 1 (Rag1) knockout (KO) mice without mature lymphocytes in streptozotocin-induced type 1 diabetic model. FTY720 (0.3mg/kg/day) was administered intraperitoneally daily for the first 4weeks with interim 3weeks then resumed for another 4weeks in 11weeks study period. T lymphocyte counts, cardiac histology, function, and fibrosis were examined in diabetic both WT and KO mice. FTY720 reduced both CD4(+) and CD8(+) T cells in diabetic WT mice. FTY720-treated diabetic WT mouse myocardium showed reduction in CD3 T cell infiltration and decreased expression of S1P1 and TGF-β1 in cardiac tissue. Fibrosis was reduced after FTY720 treatment in diabetic WT mice. Rag1 KO mice exhibited no CD4(+) and CD8(+) T cells in the blood and CD3 T cells in the heart. Diabetic Rag1 KO mouse hearts appeared no fibrosis and exhibited preserved myocardial contractility. FTY720-induced antifibrosis was abolished in diabetic Rag1 KO mice. These findings demonstrate that chronic administration with FTY720 induces lymphopenia and protects diabetic hearts in WT mice whereas FTY720 increases cardiac fibrosis and myocardial dysfunction in diabetic Rag1 KO mice without mature lymphocytes.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
authors: Chowdhury S
authors: CS
authors: Abdullah
authors: Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
authors: Zhao
authors: Z
authors: Li
authors: Department of Biology and Microbiology, College of Agriculture and Biological Sciences, South Dakota State University, Brookings, SD 57007, USA.
authors: Xiuqing
authors: X
authors: Wang
authors: Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA; Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA 95757, USA. Electronic address: zhuqiu.jin@cnsu.edu.
authors: Zhu-Qiu
authors: ZQ
authors: Jin
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000276:immunology*; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy / Q000276:immunology*; D005355:Fibrosis; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D018398:Homeodomain Proteins / Q000235:genetics; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D018398:Homeodomain Proteins; D053773:Transforming Growth Factor beta1; C064658:RAG-1 protein; D000068876:Fingolimod Hydrochloride
keywords: Diabetic cardiomyopathy; Fingolimod (FTY720); Myocardial fibrosis; Sphingosine 1-phosphate; T lymphocytes