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Signal transduction in atherosclerosis: integration of cytokines and the eicosanoid network
1Department of Biochemistry, Cornell University Medical College, New York, New York 10021.
Insights
Atherosclerosis involves cholesterol dysregulation and cell buildup in vessel walls. Endothelial cells control cholesterol transport via signaling pathways, influencing cell function and arterial health.
Area of Science:
- Cardiovascular Biology
- Cellular Signaling
- Metabolic Diseases
Background:
- Atherosclerosis is a vascular disease characterized by cholesterol metabolism dysregulation and cellular accumulation within the arterial wall.
- The endothelium plays a critical role in maintaining vascular homeostasis, including regulating cholesterol trafficking in smooth muscle cells and macrophages.
- Endothelial functions such as inflammation, vascular reactivity, and smooth muscle cell proliferation are linked to cholesterol accretion.
Purpose of the Study:
- To review regulatory mechanisms of transmembrane signal transduction in atherosclerosis.
- To explore how protein phosphorylation influences cellular responses to ligands, affecting cholesterol delivery and trafficking.
- To discuss the role of cell-to-cell communication ('cross-talk') in regulating cholesterol metabolism.
Main Methods:
- Review of studies on transmembrane signal transduction mechanisms.
- Analysis of data on the sequential action of biological response modifiers.
- Examination of cross-talk phenomena between signaling pathways.
Main Results:
- Transmembrane signaling pathways, involving protein phosphorylation, cooperatively control cellular responses to ligands.
- Eicosanoids and cytokines released from one cell activate receptors on neighboring cells, a phenomenon known as 'cross-talk'.
- Cross-talk between phosphorylation reactions (e.g., protein kinases A, C, tyrosine kinase) and lipid signaling systems impacts cholesterol metabolism.
Conclusions:
- Phosphorylation-mediated transmembrane signaling is crucial for regulating cholesterol homeostasis in vascular cells.
- Cell-cell communication ('cross-talk') among signaling pathways significantly impacts cholesterol delivery, processing, and efflux.
- Understanding these complex signaling networks offers insights into therapeutic strategies for atherosclerosis.
Abstract:
Atherosclerosis can be defined in broad terms as a vascular disease accompanied by dysregulation of cholesterol metabolism and the accumulation of smooth muscle cells and macrophages within the vessel wall. At the interface of the blood and the vessel wall is the endothelium, which actively participates in a plethora of critical homeostatic functions in addition to affecting cholesterol trafficking in the underlying smooth muscle cell and macrophage. These events include: 1) inflammation resulting in release of cytokines, 2) changes in vascular reactivity causing release of endothelial cell derived relaxing factor (EDRF) and PGI2, and 3) control of vascular smooth cell proliferation via release of growth factors and growth suppressor molecules. Each process has been linked to the regulation of cholesterol accretion in the arterial cell. Furthermore, each homeostatic process is regulated by transmembrane signaling mechanisms at the lipid-protein interface of the membrane. Data have emerged recently indicating that biological response modifiers that trigger transmembrane signaling work in a sequential manner to control cell function. We review studies of the regulatory mechanisms of transmembrane signal transduction that advance the concept that phosphorylation of the specific protein components of the receptor machinery may result in a cooperative cellular response to ligands that will ultimately affect cholesterol delivery and trafficking within cells. We review recent data demonstrating that eicosanoids and cytokines released from one cell activate their receptors on neighboring cells, and interact with each other during this "cross-talk phenomenon." Cross-talking among phosphorylation reactions involving, for example, protein kinases A and C and tyrosine protein kinase, coupled with the highly regulated eicosanoid pathways and the diacylglycerol-phosphatidyl inositol (DG-PI) system, are discussed in terms of their metabolic impact on cholesterol delivery, intracellular processing, and efflux.