Abstract 17336: The Direct Renin Inhibitor Aliskiren Prevented Onset of the Components of the Metabolic Syndrome in a Novel Mouse Model
The metabolic syndrome is a constellation of cardiovascular risk factors including insulin resistance, obesity and hypertension. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin and lipid metabolism in liver, and downregulates inflammatory response in activated T-lymphocytes. Null mutation of Ceacam1 (Cc1−/−) recapitulates the pathophysiology of the metabolic syndrome in humans. Specifically, it causes insulin resistance due to impaired insulin clearance, visceral obesity, dyslipidemia, hepatic steatosis, hypertension and atherosclerosis. The effect of direct renin inhibitors on the metabolic syndrome is still undetermined; in part due to a lack of an animal model which closely mimics the human state. We herein tested whether treatment with the direct renin inhibitor, aliskiren, prevents the metabolic syndrome in Cc1−/− mice. Two month-old Cc1−/− mice were administered aliskiren in drinking water for four months before metabolic and cardiovascular phenotypic analyses were performed. Aliskiren treatment significantly reduced systolic blood pressure measured by tail-cuff (127 ± 7.0 versus 158 ± 8.4 in Cc1−/− mice; n= 5/group; p < 0.01). It also increased insulin clearance, as assessed by plasma insulin-to- C peptide ratio (9.1 ± 0.6 versus 5.7 ± 0.6; n = 7/group; p < 0.01). Aliskiren significantly decreased both body weight (34.4 ± 0.8 versus 39.8 ± 1.7; n = 8/group; p < 0.05) and visceral obesity (2.99 ± 0.3 versus 4.20 ± 0.1; n = 10/group; p < 0.01). Quantitative Real-time PCR analysis revealed a reduction in mRNA levels of F4/80 macrophage marker, TNFα, vascular adhesion molecule 1 (VCAM1), and CD3+T cells in aorta. Direct renin inhibition protected against the onset of the metabolic syndrome in this animal model. This effect of aliskiren is reported for the first time in our model. Furthermore, if this holds true in humans, this would be a significant effect for this class of medication on the outcome of metabolic syndrome.
- © 2010 by American Heart Association, Inc.