Sphingosine-1-Phosphate Prevents Vascular Inflammation and Diabetic Complications

Vascular complications in Type 1 diabetes (nephropathy, atherosclerosis, and loss of limb function), are initiated by inflammation. Inflammation occurs when endothelial cells (EC) that line blood vessels become activated by high levels of blood glucose. These activated EC release molecules into the blood that recruit monocytes to move near the activated EC. Monocytes are blood cells that normally repair damaged tissue (they work like Pac-man to destroy harmful cellular products). In Type 1 diabetes, this repair process has gone haywire. Thus, in diabetes, both the endothelial cells and the monocytes release damaging molecules and there is no switch available to turn them off. This amplified process produces tissue damage that cannot be easily repaired.

Our grant focuses on a novel sphingolipid, sphingosine-1-phosphate, (S1P) that we have found to be anti-inflammatory; i.e. this lipid prevents these early events of inflammation. We propose to study S1P in detail to understand how it prevents monocyte and endothelial activation in diabetes using diabetic db/db mice. We will isolate monocytes and endothelial cells for db/db mice to study how S1P works to block activation of these cells. Then, we will inject S1P into db/db mice in vivo to este the hypothesis that S1P can prevent monocyte and andothelial activation in vivo. We will also test whether S1P reduces atherosclerosis in another diabetic mouse model of atherosclerosis.