A biclustering approach to analyze drug effects on extracellular matrix remodeling post-myocardial infarction

Abstract

Extracellular matrix (ECM) remodeling is an important process to determine the functional and geometric changes of the left ventricle (LV) post-myocardial infarction (MI). Currently, little research has been performed to determine key factors associated with extracellular matrix remodeling post-ML We have collected the expression levels of 84 genes in LV extracellular matrix from wild type C57BL/6J mice at day 0 (control group), day 28 (MI saline group), and day 28 MI groups treated with Aliskiren, Valsartan, and a combination of these two drugs, given from 3 h post-MI (number=6 each group). Further, we have categorized these genes using sparse singular value decomposition (SSVD) based biclustering algorithm with measurement noises considered. Our results identified the 10 most significant genes in the infarct region, and these genes were cadherin-1, collagen I and IL connective tissue growth factor, matrix metalloproteinase-3, neural cell adhesion molecule-2, osteopontin, thrombospondin-1, Tissue inhibitor of metallopreteinases-1, and tenascin C. We also identified the 15 most significant genes in the non-infarct region, which shared 6 significant genes with the infarct region (collagen IL connective tissue growth factor, matrix metalloproteinase-3, osteopontin, thrombospondin-1, and tenascin C). We then analyzed pathways enriched by the identified significant genes. Interestingly, cell death and adhesion pathways were the most significant functions identified in the infarct region while cell adhesion, cell migration, and inflammatory pathways were enriched in non-infarct region, suggesting their effect on the LV remodeling process. Our results provide a rationale for future research that target these pathways.