87 - Peroxisome Proliferator-Activated Receptors and the Endothelium

Summary

The endothelium is a biologically active, dynamic transducer of diverse inputs to the arterial wall and indeed the entire organism. In perhaps an analogous manner, peroxisome proliferator-activated receptors (PPARs) are biological integrators linking various proximal signals to multiple, specific cellular responses through transcriptional regulation (1,2). PPARs perform this function as nuclear receptors that are ligand-activated transcription factors (3). Through PPAR activation, inputs such as lipid metabolism, dietary intake, and drug therapy are coupled to nuclear responses, thus regulating entire cassettes of PPAR target genes (4). The complexity of the PPAR system allows this programmed response to be specific, carefully controlled, and integrated into feedback loops that coordinate systemic responses. The evidence for PPAR expression and activity in the endothelium identifies these biological transcriptional integrators as important contributors to endothelial biology (5). Given known PPAR control of pathways such as lipid metabolism, insulin sensitivity, adipogenesis, and energy balance, as well as recent data for PPAR involvement in inflammation and atherosclerosis (6), their relevance to endothelial cell (EC) transcriptional responses is apparent. After briefly reviewing PPARs in general, this chapter considers more recent data regarding endothelial PPAR responses.

HISTORY AND EVOLUTIONARY CONSIDERATIONS

The discovery of the nuclear hormone receptor family, beginning with the identification of the growth hormone receptor (GHR) in 1985, unearthed a critical molecular link between hormonal signaling cascades and the transcriptional control of specific gene cassettes (7). The following decade was marked by an explosion in the field of nuclear hormone receptor biology due to the realization that this superfamily of receptors regulates a broad array of physiologic processes ranging from reproduction to bone metabolism to nutrient control of carbohy-drate and lipid metabolism.