Microarray and large-scale in silico-based identification of genes functionally related to Haptoglobin and/or Hemopexin

Haptoglobin and Hemopexin are plasma acute phase proteins that bind with high-affinity hemoglobin and heme, respectively. They play a key role in the protection against oxidative stress and inflammation. To dissect in more detail the mechanism of action of Haptoglobin and Hemopexin, it is important to identify their downstream effectors as well as genes functionally related to them. To this end, we performed a cDNA microarray analysis to compare gene expression profiles of the liver of Haptoglobin and Hemopexin single and double null mice to that of wild-type controls. Then, to extract the best candidates considered to be functionally related to Haptoglobin and/or Hemopexin from microarray-derived gene lists, we used a bioinformatic approach consisting in the screening of published microarray data for genes showing coexpression with Haptoglobin or Hemopexin. This strategy allowed us to identify a group of genes coexpressed with Haptoglobin or Hemopexin and transcriptionally modulated by their lack. These genes present a high probability to be functionally related to Haptoglobin and Hemopexin. Based on literature data, we picked up from this group of genes the ras suppressor Rsu1, the member of the G-protein signal transduction family Gnai2, and the cytokine Mdk as the best candidates mediating the anti-inflammatory action of Haptoglobin and Hemopexin.