Novel control of cAMP-regulated transcription in vascular endothelial cells

• Published in: Biochemical Society transactions Vol. 40; no. 1; p. 1
• Main Authors: Milne, Gillian R, Palmer, Timothy M, Yarwood, Stephen J
• Format: Journal Article
• Language: English
• Published: England 01.02.2012
• Subjects: CCAAT-Enhancer-Binding Protein-beta - metabolism; CCAAT-Enhancer-Binding Protein-delta - metabolism; Cells, Cultured; Cyclic AMP - metabolism; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Gene Expression Regulation; Guanine Nucleotide Exchange Factors - metabolism; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Inflammation - metabolism; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Transcription, Genetic
• DOI: 10.1042/BST20110606

Chronic inflammatory diseases, such as atherosclerosis, are a major cause of death and disability in the developed world. In this respect, although cholesterol obviously plays a predominant role in atherosclerosis, targeting inflammation at lesion sites may be just as important. Indeed, elevated IL-6 (interleukin 6) levels are as strongly associated with coronary heart disease as increased cholesterol. We have been investigating novel cAMP-regulated pathways that combat the action of pro-inflammatory cytokines, such as IL-6 and leptin, in the VECs (vascular endothelial cells) of the circulatory system. In this respect, we have begun to unravel new molecular mechanisms by which the cAMP/Epac1 (exchange protein directly activated by cAMP 1)/Rap1 pathway can initiate a rigorous programme of protective anti-inflammatory responses in VECs. Central to this is the coupling of cAMP elevation to the mobilization of two C/EBP (CCAAT/enhancer-binding protein) family transcription factors, resulting in the induction of the SOCS3 (suppressor of cytokine signalling 3) gene, which attenuates pro-inflammatory cytokine signalling in VECs. These novel 'protective' mechanisms of cAMP action will inform the development of the next generation of pharmaceuticals specifically designed to combat endothelial inflammation associated with cardiovascular disease.