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Is T-cadherin a missing link between insulin signaling and endothelial dysfucntion?
| Third-party funded project |
| Project title |
Is T-cadherin a missing link between insulin signaling and endothelial dysfucntion? |
| Principal Investigator(s) |
Resink, Thérèse J.
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| Co-Investigator(s) |
Erne, Paul
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| Organisation / Research unit |
Departement Biomedizin / Signal Transduction (Resink/Erne) |
| Project start |
01.04.2011 |
| Probable end |
31.03.2014 |
| Status |
Completed |
| Abstract |
Background: Cardiovascular and metabolic diseases are an escalating public health issue worldwide due to increasingly aging populations and sedentary lifestyles and also the rising prevalence of obesity in children. Endothelial dysfunction (ED) and insulin resistance are frequently co-morbid states in cardiovascular and metabolic disorders. The clinical relevance of this coupling is highlighted by the findings that specific therapeutic interventions targeting insulin resistance often also ameliorate ED (and vice versa). The state of insulin resistance encompasses abnormalities in both the metabolic and hemodynamic actions of insulin. In the context of the vascular system, insulin resistance manifests as impaired vasodilation, microvessel disease, vascular inflammation and atherosclerotic lesion formation. Insulin exerts its vascular effects primarily by augmenting availability of endothelium-derived NO via activation of the PI3K/Akt signaling pathway, and impairment of this may be a triggering factor in the initiation and progression of atherosclerosis in insulin resistance syndromes. Molecular mechanisms for impairments in vascular actions of insulin remain incompletely characterized.
The cadherins comprise a large family of cell-surface proteins involved in cell-cell interactions and signaling. They exhibit cell-type and developmental specificity in expression and are aberrantly regulated in several human malignancies. Our research over the past decade has focused on the role of atypical GPI-anchored T-cadherin (T-cad) in regulation of endothelial cell (EC) function. T-cad is highly expressed in the vessel wall. It is upregulated in vivo within the endothelium of atherosclerotic lesional tissue and in vitro on EC subjected to activation/stress. T-cad promotes EC proliferation, migration, survival under stress conditions and angiogenesis. EC-derived T-cad can be detected in the circulation of patients with atherosclerosis and in association with ED. Genome-wide association studies point toward a role for T-cad in progression of hypertension, which is also associated with ED and insulin resistance and increased risk of atherosclerosis. T-cad has also been shown to bind adiponectin, an adipokine that critically modulates insulin resistance and atherogenesis. Our pilot studies show that T-cad attenuates insulin-induced signaling and angiogenesis in EC in vitro.
Hypothesis: We hypothesize that T-cad constitutes a regulatory component of insulin signaling pathways in EC. To test this hypothesis our primary goals are to examine whether (1) T-cad regulates signaling responses of EC to insulin and related functional downstream events including NO biosynthesis and angiogenesis; (2) T-cad utilizes components of the insulin signaling pathway to elicit its own effects in EC; (3) T-cad levels in human plasma correlate with insulin resistance.
Significance: Elucidation of cross-talk between T-cad and insulin signaling will give new insights into the cellular mechanisms responsible for vascular insulin resistance and associated vascular dysfunction. Identification of relationships between plasma T-cad, vascular insulin resistance and metabolic insulin resistance is relevant to efforts aimed at advancing integrated therapeutic approaches for simultaneous treatment of cardiovascular and metabolic disorders. By demonstrating the ability of T-cad to interact with other hormone/growth factor receptor systems (i.e. insulin and its receptors IR and/or IGF-1R) and identifying specific mechanisms mediating that interaction this study will generate novel information on the function of atypical GPI-anchored T-cad in the endothelium. |
| Financed by |
Swiss National Science Foundation (SNSF)
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12/05/2024
Research Database / FORSCHUNGSDATENBANK
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