Expression and Regulation of Adhesion Molecules in Cardiac Cells by Cytokines

Response to Acute Hypoxia

From the Cardiology Section of the Veterans Affairs Medical Center, the Cardiovascular Research Institute, and the Department of Medicine, University of California, San Francisco.

Correspondence to Dr Joel S. Karliner, Chief, Cardiology Section, VA Medical Center, 4150 Clement St, San Francisco, CA 94121. E-mail Karliner.Joel-S{at}SanFrancisco.VA.Gov

Abstract—Adhesion molecules mediate inflammatory myocardial injury after ischemia/reperfusion. Cytokine release and hypoxia are features of acute ischemia that may influence expression of these molecules. Accordingly, we studied intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) responses to cytokines and acute hypoxia in cultured myocardial cells. Northern blot analysis and immunoassay showed that the proinflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor- stimulated concentration-dependent increases in ICAM and VCAM mRNA and protein. In both cardiac myocytes and fibroblasts, pretreatment with a specific inhibitor of nuclear transcription factor-B (NF-B) prevented cytokine induction of both molecules. We also found that inhibition of tyrosine kinase and p38/RK (stress-activated protein kinase) pathways prevented IL-1ß–induced ICAM and VCAM protein synthesis, whereas extracellular signal–regulated protein kinase (ERK1/ERK2) inhibition did not. Neither hypoxia (0% O₂ for 6 hours) alone nor hypoxia/reoxygenation had any significant effect on ICAM and VCAM mRNA. However, hypoxia did enhance IL-1ß–induced ICAM mRNA expression in myocytes. As a possible mechanism of this synergistic action on CAM expression, hypoxia induced a time-dependent increase in the DNA binding activity of both NF-B and activator protein-1 (AP-1), two transcription factors important for cell adhesion molecule expression. In contrast to the enhanced ICAM mRNA induced by IL-1ß during hypoxia, however, protein levels for this adhesion molecule were unchanged beyond IL-1ß–stimulated levels, suggesting posttranscriptional and/or posttranslational control mechanisms. We conclude that cytokines regulate ICAM and VCAM mRNA and protein in both cardiac myocytes and fibroblasts. Furthermore, adhesion molecule induction requires translocation of at least two transcription factors, NF-B and AP-1.

Key Words: cytokine • hypoxia • cell adhesion molecule • mRNA • signal transduction

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