Background:
Glucocorticoid administration impairs ischemic wound healing by inhibiting inflammation and angiogenesis via a glucocorticoid receptor (GR)-mediated transcriptional response. However, there are also apparently contradictory reports claiming protective effects of glucorticoid administration after myocardial infarction (MI). We investigated the role of the GR in myeloid cells for infarct wound healing, using GR deficient mice (GRLysMCre).
Methods and Results:
MI was induced by permanent left coronary artery ligation in GRflox (wild-type [WT] controls) and GRLysMCre mice. The 7-day mortality was significantly lower in WT compared with GRLysMCre mice. At 7 days post MI, GRLysMCre mice exhibited significantly enhanced thinning and dilatation of the infarcted wall, LV chamber enlargement and functional deterioration. This was associated with altered granulation tissue formation and impaired neoangiogenesis at the site of ischemic injury. Multicolor flow cytometric analysis and immunohistochemical studies revealed at the 2nd day post infarction less infiltrating mononuclear cells [CD11bhigh and (CD49b, NK1.1, B220, CD90, Ly6G)low] in the healing myocardium of GRLysMCre mice. Mononuclear cells were identified as monocytes (F4/80, I-Ab, CD11c)low and as macrophages/dendritic cells (F4/80, I-Ab, CD11c)high. Monocytes lacking GR, isolated from peripheral blood and spleen by magnetic-activated cell sorting 1 day after MI, displayed reduced migration capacity and increased superoxide anion production in mitochondria, which was detected by HPLC-electrochemical analysis of Mito-2-hydroxy-E+. Moreover, at day 2 and 3 we found enhanced cellular and mitochondrial oxidative stress in the healing myocardium of GRLysMCre mice.
Conclusions:
Myeloid-specific deletion of the GR increasing mitochondrial oxidative stress alters wound healing and promotes infarct expansion. Our results suggest that the GR in myeloid cells play a crucial role during cardiac repair after myocardial infarction.
