Altered Hepatic Gene Expression Profiles Associated with Myocardial Ischemia

Background–Acute coronary syndrome (ACS) is sometimes accompanied by accelerated coagulability, lipid metabolism, and inflammatory responses, which are not attributable to the cardiac events alone. We hypothesized that the liver plays a pivotal role in the pathophysiology of ACS. We simultaneously analyzed the gene expression profiles of the liver and heart during acute myocardial ischemia in mice. Methods and Results–Mice were divided into three treatment groups: sham-operation, ischemia-reperfusion (I/R), and myocardial infarction. Mice with liver I/R were included as additional controls. Marked changes in hepatic gene expression were observed after 24 hours, despite the lack of histological changes in the liver. Genes related to tissue remodeling, adhesion molecules, and morphogenesis were significantly upregulated in the livers of mice with myocardial I/R or infarction, but not in those with liver I/R. Myocardial ischemia, but not changes in the hemodynamic state, was postulated to significantly alter hepatic gene expression. Moreover, detailed analysis of the signaling pathway suggested the presence of humoral factors that intervened between the heart and liver. To address these points, we utilized isolated primary hepatocytes and showed that osteopontin released from the heart actually altered the signaling pathways of primary hepatocytes to those observed in the livers of mice under myocardial ischemia. Moreover, osteopontin stimulated primary hepatocytes to secrete vascular endothelial growth factor-A, which is important for tissue remodeling. Conclusions– Hepatic gene expression is potentially regulated by cardiac humoral factors under myocardial ischemia. These results provide new insights into the pathophysiology of ACS. C57BL/6J mice (n=46, BW 24.1±1.42 g, 8–10 weeks of age; Charles River Laboratories) were divided into the following treatment groups: sham-operated (n=11), I/R (n=10), myocardial infarction (n=10), liver I/R (n=10), and sham-operated plus hydralazine (n=5). In this study, we examined the response of hepatic gene expression to myocardial ischemia. Given the systemic inflammation that characterizes acute coronary syndromes, we postulated that regulation of hepatic genes occurs via inflammatory mediators and not via alterations in hemodynamics or hepatic perfusion. We therefore used whole genome transcriptional profiling to identify hepatic genes selectively regulated in the setting of myocardial ischemia. Moreover, detailed analysis of the signaling pathway suggested the presence of humoral factors that intervened between the heart and liver under myocardial ischemia. As a candidate humoral factors, osteopontin was further investigated. To evaluate whether the cardiac secreted protein affects hepatic gene expressions, we investigated primary hepatocytes treated with osteopontin by using microarray analysis. Affymetrix GeneChip Mouse Genome 430 2.0 Array was used to measure gene expression levels in primary hepatocytes at 8 hours after osteopontin stimulation (mock: n=3 and osteopontin: n=3).