Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans.

AIMS: Monocytes play critical roles in tissue injury and repair following acute myocardial infarction (AMI). Specifically targeting inflammatory monocytes in experimental models leads to reduced infarct size and improved healing. However, data from humans are sparse, and it remains unclear whether monocytes play an equally important role in humans. The aim of this study was to investigate whether the monocyte response following AMI is conserved between humans and mice and interrogate patterns of gene expression to identify regulated functions. METHODS AND RESULTS: Thirty patients (AMI) and 24 control patients (stable coronary atherosclerosis) were enrolled. Female C57BL/6J mice (n = 6/group) underwent AMI by surgical coronary ligation. Myocardial injury was quantified by magnetic resonance imaging (human) and echocardiography (mice). Peripheral monocytes were isolated at presentation and at 48 h. RNA from separated monocytes was hybridized to Illumina beadchips. Acute myocardial infarction resulted in a significant peripheral monocytosis in both species that positively correlated with the extent of myocardial injury. Analysis of the monocyte transcriptome following AMI demonstrated significant conservation and identified inflammation and mitosis as central processes to this response. These findings were validated in both species. CONCLUSIONS: Our findings show that the monocyte transcriptome is conserved between mice and humans following AMI. Patterns of gene expression associated with inflammation and proliferation appear to be switched on prior to their infiltration of injured myocardium suggesting that the specific targeting of inflammatory and proliferative processes in these immune cells in humans are possible therapeutic strategies. Importantly, they could be effective in the hours after AMI.

A novel diagnostic screen for defects in the Fanconi anemia pathway.

Fanconi anemia (FA) is an autosomal recessive chromosomal instability syndrome characterized by congenital abnormalities, progressive bone marrow failure, and cancer predisposition. Although patients with FA are candidates for bone marrow transplantation or gene therapy, their phenotypic heterogeneity can delay or obscure diagnosis. The current diagnostic test for FA consists of cytogenetic quantitation of chromosomal breakage in response to diepoxybutane (DEB) or mitomycin C (MMC). Recent studies have elucidated a biochemical pathway for Fanconi anemia that culminates in the monoubiquitination of the FANCD2 protein. In the current study, we develop a new rapid diagnostic and subtyping FA assay amenable for screening broad populations at risk of FA. Primary lymphocytes were assayed for FANCD2 monoubiquitination by immunoblot. The absence of the monoubiquitinated FANCD2 isoform correlated with the diagnosis of FA by DEB testing in 11 known patients with FA, 37 patients referred for possible FA, and 29 healthy control subjects. Monoubiquitination of FANCD2 was normal in other bone marrow failure syndromes and chromosomal breakage syndromes. A combination of retroviral gene transfer and FANCD2 immunoblotting provides a rapid subtyping assay for patients newly diagnosed with FA. These new FA screening assays would allow efficient testing of broad populations at risk.