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Vascular signaling pathways in the metabolic syndrome
Hiromi Rakugi1, Kei Kamide, Toshio Ogihara
1Department of Geriatric Medicine (B6), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. rakugi@geriat.med.osaka-u.ac.jp
Abstract:
There are several potential cellular and molecular pathways whereby cardiovascular risk factors act through very specific signal transduction pathways in the formation of atherosclerosis, as seen often in the metabolic syndrome. Many examples point to multiple postreceptor defects in the insulin signaling pathway in vascular tissue, however, there are differences in the insulin receptor pathway in vascular tissue compared with skeletal muscle or fat. In addition to insulin receptors, insulin may affect atherosclerotic changes in the vascular cells via stimulation of insulin-like growth factor-1 receptors and their signaling pathway. Insulin also causes activation of the vascular renin-angiotensin system in both vascular smooth muscle cells and endothelial cells. Insulin-activated tissue renin-angiotensin system leads to increased cell growth and contributes to the cause of atherosclerosis. The fact that agents that inhibit the renin-angiotensin system also block insulin-mediated renin-angiotensin system expression and cell growth reinforces the potential implication of a vascular insulin-renin-angiotensin system pathway. Finally, novel substances such as the adipokines, factors produced from fat cells, reveal new risk factors in the metabolic syndrome and offer further evidence for a link between insulin resistance and accelerated atherosclerosis.
Insights
Cardiovascular risk factors promote atherosclerosis via insulin signaling defects and activation of the vascular renin-angiotensin system. Adipokines further link insulin resistance to accelerated atherosclerosis, highlighting novel therapeutic targets.
Area of Science:
- Cardiovascular biology
- Metabolic syndrome research
- Molecular signaling pathways
Background:
- Cardiovascular risk factors contribute to atherosclerosis, particularly in metabolic syndrome.
- Insulin resistance involves postreceptor defects in vascular insulin signaling, differing from skeletal muscle and fat.
- Vascular cells are targets for insulin's effects beyond direct insulin receptors.
Purpose of the Study:
- To elucidate cellular and molecular pathways linking cardiovascular risk factors to atherosclerosis.
- To investigate insulin's role in vascular cells, including effects on insulin-like growth factor-1 receptors and the renin-angiotensin system.
- To explore the contribution of novel factors like adipokines to the insulin resistance-atherosclerosis link.
Main Methods:
- Analysis of signal transduction pathways in vascular tissue.
- Investigation of insulin receptor and insulin-like growth factor-1 receptor signaling.
- Assessment of insulin's activation of the vascular renin-angiotensin system.
- Evaluation of adipokines as novel risk factors.
Main Results:
- Insulin signaling defects in vascular tissue are implicated in atherosclerosis.
- Insulin activates the vascular renin-angiotensin system, promoting cell growth and atherosclerosis.
- Inhibition of the renin-angiotensin system blocks insulin-mediated effects, supporting a vascular pathway.
- Adipokines represent new risk factors connecting insulin resistance and atherosclerosis.
Conclusions:
- Multiple pathways, including insulin signaling and the vascular renin-angiotensin system, mediate atherosclerosis in metabolic syndrome.
- Targeting the insulin-renin-angiotensin system may offer therapeutic strategies for atherosclerosis.
- Adipokines provide further evidence for the link between insulin resistance and accelerated atherosclerosis.