Published online before print August 3, 2007

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(American Journal of Pathology. 2007;171:820-828.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061076

Selective Impairment of Nuclear Factor-B-Dependent Gene Transcription in Adult Cardiomyocytes

Relevance for the Regulation of the Inflammatory Response in the Heart

Jimena Cuenca^*, Nora Goren^*, Patricia Prieto^*, Paloma Martín-Sanz^* and Lisardo Boscá^*

From the Instituto de Investigaciones Biomédicas Alberto Sols (Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid^* and the Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain

The ability of neonatal and adult cardiomyocytes to activate the nuclear factor (NF)-B pathway in response to lipopolysaccharide and interleukin-1ß challenge has been investigated and compared with that of peritoneal macrophages. The activation of the IB kinase and the phosphorylation and degradation of IB and IBß was much lower in adult cardiomyocytes than in the neonatal counterparts and macrophages. This restricted activation of the NF-B pathway resulted in a significant reduction in the time of nuclear activation of NF-B, as deduced by electrophoretic mobility shift assays and in the transcription of target genes, such as IB, cyclooxygenase-2 (COX-2) and nitric-oxide synthase-2 (NOS-2). Studies on chromatin immunoprecipitation showed binding of NF-B proteins to the regulatory B sites identified in the promoters of the IB, COX-2, and NOS-2 genes in macrophages and, to a lower extent, in neonatal cardiomyocytes. The binding to these B sites in adult cardiomyocytes was observed only in the IB promoter and was minimal or absent in the COX-2 and NOS-2 promoters, respectively, suggesting a restricted activation of NF-B-regulated genes in these cells. These data indicate that the function of the NF-B pathway in adult cardiomyocytes is limited in time, which results in the expression of a reduced number of genes and provides a functional explanation for the absence of NOS-2 inducibility in these cells under proinflammatory conditions.