Endothelial Gene Expression Associated With Early Coronary Atherosclerosis

We examined feasibility of a unique approach towards gaining insight into heritable risk for early atherosclerosis: surveying gene expression by endothelial cells from living subjects. Subjects <50 years old (mean 37, range 22-49) without obstructive coronary artery disease underwent coronary reactivity testing that identified them as having normal (NL) or abnormal (ABNL) coronary endothelial function. Cultures of Blood Outgrowth Endothelial Cells (BOEC) from 6 NLs and 13 ABNLs passed rigorous quality control and were used for microarray assessment of gene expression. Of nine genes differentially expressed at FDR<0.1%, we here focus upon ABNLs having elevated expression of HMGB1 which we unexpectedly found to be linked to low LAMC1 expression. This was corroborated by three of our past studies and confirmed bio-functionally. Compared to NL BOEC, ABNL BOEC released 13±3 fold more HMGB1 in response to LPS; and they deposited one-tenth as much LAMC1 into collagen subendothelial matrix during culture. Clinical follow-up data are provided for 4 NLs (followed 13.4±0.1 yr) and for 12 ABNLs (followed 9.1±4.5 yr). The known pathogenic effects of high-HMGB1 and low-LAMC1 predict that the combination would biologically converge upon the focal adhesion complex, to the detriment of endothelial shear responsiveness. This gene expression pattern may comprise a heritable risk state that promotes early coronary atherosclerosis. If so, the testing could be applied even in childhood, enabling early intervention. This approach offers a way to bridge the information gap between genetics and clinical phenotype. 6 subjects with normal coronary endothelial function, and 13 subjects with abnormal coronary endothelial function. All were adults <45 years old.