High plasma endothelin-1 (ET-1) level has been associated with diabetic cardiovascular and renal complications, which remained prevalent despite good glycemic control. Since endothelial dysfunction, which is characterized by enhanced ET-1 secretion, plays an important role in mediating diabetic complication, we hypothesized that disruption of ET-1 in endothelial cell will be protective against cardiac and renal complication of diabetes. To test this hypothesis, we injected streptozotocin to Vascular Endothelial cell Specific Endothelin-1 Knockout (VEETKO) mice, of which ET-1 expression in major organs including heart and kidney were reduced by 60%, and to their wild type (WT) littermates. Six months of diabetes increased systolic blood pressure (SBP) similarly in both genotypes, with DM-VEETKO mice have remained lower SBP than DM-WT mice (124±1.08 vs. 131.33±1.33 mmHg, p<0.01, n=8 each). Diabetes also exaggerated the difference in cardiac ET-1 mRNA expression between both groups. The heart of DM-VEETKO mice showed lower area of interstitial fibrosis as compared to DM-WT mice, and this is associated with lower expression of fibrotic genes (TGF-β, CTGF and Collagen-1), higher capillary density (as measured by CD-31 staining) and higher VEGF mRNA expression. Furthermore, eight months of diabetes decreased cardiac systolic function of all mice, however, the decrease is significantly attenuated in DM-VEETKO mice (fractional shortening 45.67±0.61 vs. 38.27±2.2%, p<0.01, n=4 each). Similarly, DM-VEETKO mice also preserved renal function. Diabetes caused an increase in urinary protein excretion with the values in DM-VEETKO mice being approximately one fifth of DM-WT mice (30.12±10.09 vs. 170±23.19 mg/dl, p<0.01, n=6 each) Morphologically, DM-VEETKO mice have less glomerular fibrosis which is associated with lower expression of ICAM-1, and further leads to lower glomerular macrophage recruitment. In conclusion, these findings indicate that disruption of ET-1 in endothelial cell is significantly attenuated diabetic cardiovascular and renal complication in streptozotocin-induced diabetic mice model, and may provide additional basic rationales for the use of ET-1 blockade for the prevention of cardiac and renal complication of diabetes.
Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation
