Key result
In post-MI sheep and in vitro models, mitral valve endothelial cells express CD45, and a CD45 phosphatase inhibitor blocked hallmarks of endothelial-to-mesenchymal transition and fibrosis.
CD45 phosphatase activity is required for endothelial-to-mesenchymal transition in mitral valve endothelial cells, highlighting a novel mechanism in post-MI mitral valve adaptation and fibrosis.
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MV endothelial CD45+ cells may drive post-MI regurgitation progression; extends randomized large-animal data to valvular endothelial responses.
Rationale : Ischemic mitral regurgitation, a complication after myocardial infarction (MI), induces adaptive mitral valve (MV) responses that may be initially beneficial but eventually lead to leaflet fibrosis and MV dysfunction. We sought to examine the MV endothelial response and its potential contribution to ischemic mitral regurgitation. Objective : Endothelial, interstitial, and hematopoietic cells in MVs from post-MI sheep were quantified. MV endothelial CD45, found post MI, was analyzed in vitro. Methods and Results : Ovine MVs, harvested 6 months after inferior MI, showed CD45, a protein tyrosine phosphatase, colocalized with von Willebrand factor, an endothelial marker. Flow cytometry of MV cells revealed significant increases in CD45 + endothelial cells (VE-cadherin + /CD45 + /α-smooth muscle actin [SMA] + and VE-cadherin + /CD45 + /αSMA− cells) and possible fibrocytes (VE-cadherin − /CD45 + /αSMA + ) in inferior MI compared with sham-operated and normal sheep. CD45 + cells correlated with MV fibrosis and mitral regurgitation severity. VE-cadherin + /CD45 + /αSMA + cells suggested that CD45 may be linked to endothelial-to-mesenchymal transition (EndMT). MV endothelial cells treated with transforming growth factor-β1 to induce EndMT expressed CD45 and fibrosis markers collagen 1 and 3 and transforming growth factor-β1 to 3, not observed in transforming growth factor-β1–treated arterial endothelial cells. A CD45 protein tyrosine phosphatase inhibitor blocked induction of EndMT and fibrosis markers and inhibited EndMT-associated migration of MV endothelial cells. Conclusions : MV endothelial cells express CD45, both in vivo post MI and in vitro in response to transforming growth factor-β1. A CD45 phosphatase inhibitor blocked hallmarks of EndMT in MV endothelial cells. These results point to a novel, functional requirement for CD45 phosphatase activity in EndMT. The contribution of CD45 + endothelial cells to MV adaptation and fibrosis post MI warrants investigation.
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Bischoff et al. (2016) studied Ischemic mitral regurgitation post-myocardial infarction. CD45 phosphatase inhibitor and TGF-β1 (in vitro) / Inferior MI (in vivo) vs. Sham-operated and normal sheep (in vivo) / untreated cells (in vitro) was evaluated on CD45 expression and endothelial-to-mesenchymal transition (EndMT) markers. In post-MI sheep and in vitro models, mitral valve endothelial cells express CD45, and a CD45 phosphatase inhibitor blocked hallmarks of endothelial-to-mesenchymal transition and fibrosis.
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