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 (S1P 1 )‐mediated signaling directs T‐lymphocyte trafficking. Effects of T‐cell S1P 1 activation on cardiac fibrosis in a murine diabetic model remain to be explored. For this purpose, conditional T‐cell S1P 1 knockout (TS1P 1 KO) mice generated by crossing S1pr 1 loxP/loxP mice with Lck‐Cre mice were used in a model of streptozotocin‐induced diabetic cardiomyopathy. The TS1P 1 KO mice exhibited sustained deficiency of both CD4 + and CD8 + T cells in the blood. The TS1P 1 KO 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, TS1P 1 KO diabetic mice had improved cardiac function and alleviated cardiac fibrosis detected after 11 wk of diabetic induction. Our results indicate that T‐cell S1P 1 signaling activation plays a dual role in the pathogenesis of cardiac fibrosis with respect to the levels of glucose: T‐cell S1P 1 activation 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