Abstract 19116: Depletion of T Lymphocytes Exerts Cardioprotection and Antifibrotic Effect in Streptozotocin-Induced Type 1 Diabetic Mice
Background and Aims: T lymphocytes infiltration into myocardium has been observed in both type 1 and type 2 diabetic patients. However, effects of T cells on cardiac function and survival as well as fibrosis in a diabetic model remain to be determined.
Methods: In this study, depletion of T cells was achieved by using pharmacological approach (fingolimod, a sphingosine 1-phosphate receptor modulator) and genetic approach (Rag1 knockout mice without mature lymphocytes). Type 1 diabetes was induced by intraperitoneal injection of streptozotocin (STZ) for five consecutive days with small dose (50 mg/kg) in both C57BL/6J mice and Rag1 mutant mice. Treatment with Fingolimod (0.3 mg/kg/day, i.p.) was performed in STZ diabetic mice. Body weight of mice was monitored twice a week. Fasting blood glucose level was detected after 4 weeks and 11 weeks of STZ administration. At the end of 11 weeks, blood T cells (CD4+ and CD8+) counting was conducted with flow cytometry. Serum insulin content was measured with ELISA. Infiltration of T cells (CD3+ positive staining) into the myocardium of mice was observed with immunohistochemistry method in paraffin sections. The fibrosis of myocardium was quantified by using trichrome staining. Cardiac contractile force was recorded with Langendorff heart perfusion system. Apoptosis of hearts was detected with TUNEL staining.
Results: Fingolimod had no effects on body weight and glucose level (478+/-20 mg/dl vs 426+/-34 mg/dl in vehicle group, p=n.s.). Fingolimod significantly reduced the blood T cells (CD4+ cells: 0.16+/-0.12% vs 7.07+/-0.68% in vehicle group, P<0.01, n=4-5 per group) in C57BL/6J mice. Fingolimod also enhanced cardiac contractility and reduced fibrosis as well as apoptosis of the myocardium in C57BL/6J mice. Compared to wild-type (B6), Rag1 mutant mice remained the high blood glucose level in STZ model (447+/-36 mg/dl, n=11). However, cardiac fibrosis was reduced and cardiac contractile force was enhanced in Rag1 mutant mice.
Conclusions: Depletion of T cells in the circulation with pharmacological agent-Fingolimod or Rag1 mutation without mature lymphocytes renders hearts more resistant to the cardiac injury caused by diabetes.
- © 2013 by American Heart Association, Inc.