Targeted deletion of T‐cell S1P receptor 1 ameliorates cardiac fibrosis in streptozotocin‐induced diabetic mice

Infiltration of T cells is associated with patients who have diabetes at an increased risk of heart attack. T-cell sphingosine 1-phosphate receptor 1 (S1P1)-mediated signaling directs T-lymphocyte trafficking. Effects of T-cell S1P1 activation on cardiac fibrosis in a murine diabetic model remain to be explored. For this purpose, conditional T-cell S1P1 knockout (TS1P1KO) mice generated by crossing S1pr1loxP/loxP mice with Lck-Cre mice were used in a model of streptozotocin-induced diabetic cardiomyopathy. The TS1P1KO mice exhibited sustained deficiency of both CD4+ and CD8+ T cells in the blood. The TS1P1KO vehicle control mouse hearts featured an altered phenotype characterized by increased myocardial fibrosis and reduced cardiac contractility under normal levels of glucose. Compared with littermate diabetic mice, TS1P1KO diabetic mice had improved cardiac function and alleviated cardiac fibrosis detected after 11 wk of diabetic induction. Our results indicate that T-cell S1P1 signaling activation plays a dual role in the pathogenesis of cardiac fibrosis with respect to the levels of glucose: T-cell S1P1activation exerts antifibrotic effects in normoglycemia but exacerbates fibrosis under hyperglycemia.—Abdullah, C. S., Jin, Z.-Q. Targeted deletion of T-cell S1P receptor 1 ameliorates cardiac fibrosis in streptozotocin-induced diabetic mice. FASEB J. 32, 5426–5435 (2018). www.fasebj.org