TIE-ing off atherosclerosis

Abstract

A Vanderbilt University School of Medicine team has found that knocking out tyrosine kinase receptor 1 on vascular endothelial cells in mice decreases the formation of atherosclerotic plaques. 1 Now the team plans to study the mechanism underlying the therapeutic effect. The findings could represent a new indication for sanofi-aventis Group, which has licensed at least two therapies targeting tyrosine kinase receptor proteins in cancer and wound healing.Previous work in mice by the Vanderbilt researchers and other labs showed that tyrosine kinase receptor 1 (Tie1) is widely expressed in an embryo's endothelial tissues, 2,3 but in adults it is upregulated only in the vascular endothelium at valves and vessels that are prone to atherosclerotic lesions. 4 Based on those findings, H. Scott Baldwin, professor of pediatric cardiology and cell and developmental biology at Vanderbilt, hypothesized that targeting TIE1 in the adult vasculature could help treat atherosclerosis.To test that hypothesis, his team knocked out Tie1 in the vascular endothelium of apolipoprotein E (Apoe) −/− mice, which are standard mouse models of hypercholesterolemia and atherosclerosis.At 12 and 24 weeks, endothelial-specific Tie1 knockout decreased aortic atherosclerotic lesions by 68% and 70% compared with those in control animals (p<0.0005 and p<0.006, respectively). Those reductions were associated with less proinflammatory macrophage infiltration and lower expression of two biomarkers of inflammation: rho-associated coiled-coil containing protein kinase 1 (Rock1) and Rock2.The Tie1-deficient animals had serum cholesterol and triglyceride levels similar to those in control mice, suggesting that the receptor's antiatherosclerotic mechanism is distinct from that of the statins, which lower cholesterol by targeting HMG-CoA reductase, the molecule's biosynthetic enzyme."This prophylactic alleviation of atherosclerosis burden by the reduction of Tie1 expression and signaling points to Tie1 as an attractive candidate for targeted therapeutic approaches, " the authors wrote in The Journal of Clinical Investigation.