Myeloperoxidase oxidized LDL interferes with endothelial cell motility through miR-22 and heme oxygenase 1 induction: possible involvement in reendothelialization of vascular injuries.

Cardiovascular disease linked to atherosclerosis is the leading cause of death worldwide. Atherosclerosis is mainly linked to dysfunction in vascular endothelial cells and subendothelial accumulation of oxidized forms of LDL. In the present study, we investigated the role of myeloperoxidase oxidized LDL (Mox-LDL) in endothelial cell dysfunction. We studied the effect of proinflammatory Mox-LDL treatment on endothelial cell motility, a parameter essential for normal vascular processes such as angiogenesis and blood vessel repair. This is particularly important in the context of an atheroma plaque, where vascular wall integrity is affected and interference with its repair could contribute to progression of the disease. We investigated in vitro the effect of Mox-LDL on endothelial cells angiogenic properties and we also studied the signalling pathways that could be affected by analysing Mox-LDL effect on the expression of angiogenesis-related genes. We report that Mox-LDL inhibits endothelial cell motility and tubulogenesis through an increase in miR-22 and heme oxygenase 1 expression. Our in vitro data indicate that Mox-LDL interferes with parameters associated with angiogenesis. They suggest that high LDL levels in patients would impair their endothelial cell capacity to cope with a damaged endothelium contributing negatively to the progression of the atheroma plaque.

HDAC7 regulates apoptosis in developing thymocytes.

Central immune tolerance is established in the thymus for T cells via a complex selection process that involves interactions between CD4+CD8+ double-positive thymocytes and antigen-presenting cells. Cells that express antigen receptors interacting strongly with self peptide MHC complexes are deleted from the repertoire via activation-induced apoptosis, a process termed negative selection. Cells that express an appropriate signal are positively selected and mature into single positive naïve T cells, either CD4 or CD8 positive. The balance between positive and negative selection is thought to play a critical role in the elimination of self-reactive clones and in the establishment of central immune tolerance. We have recently reported that HDAC7, a class II histone deacetylase, is highly expressed in CD4+CD8+ double positive thymocytes. HDAC7 inhibits Nur77 expression, an orphan receptor involved in antigen-induced cell death and in negative selection. The inhibitory effect of HDAC7 on the Nur77 promoter is mediated via the transcription factor MEF2D. During T cell receptor activation, HDAC7 is exported from the nucleus leading to the derepression of Nur77 expression and the induction of apoptosis. These observations define HDAC7 as a regulator of Nur77 and apoptosis in developing thymocytes and indicate that HDAC7 is likely to play an important role in the control of central immune tolerance.