| Summary: | Background: Currently, the optimal long-term therapy for end stage heart failure is heart transplantation. Cardiac allograft vasculopathy contributes to a significant number of deaths following transplantation. This vasculopathy is related to early endothelial injury sustained at the time of organ transplantation and to persistent endothelial injury as a result of cytotoxic immunosuppression, as well as chronic rejection.
Epidermal growth factor-like domain 7 (Egfl7), is expressed in endothelial cells upon arterial injury and may have a role in maintaining vascular endothelial integrity and regeneration following injury. Similarly, novel pharmacologic agents such as Bosentan, an endothelin-1 antagonist, and Cilostazol, a phosphodiesterase 3 inhibitor, have been demonstrated to attenuate calcineurin inhibition induced endothelial dysfunction and neointimal hyperplasia, respectively. We hypothesized that, 1) Egfl7 will attenuate endothelial activation, cell adhesion molecule expression and neutrophil adhesion following simulated ischemia-reperfusion injury or exposure to calcineurin inhibition and that, 2) Bosentan and Cilostazol will inhibit neointimal hyperplasia following endothelial injury in a mouse model of vascular injury.
Methods: Human coronary artery endothelial cells were subjected to hypoxia-reoxygenation injury or the calcineurin inhibitors Cyclosporine A and Tacrolimus to examine the effects of Egfl7 on these injury mechanisms. Cell adhesion molecule expression, neutrophil adhesion to endothelial cells, and NF-κB activation were measured. Cell adhesion molecule and Egfl7 expression were also examined in a mouse model of neointimal. This model was used to examine the effects of Bosentan and Cilostazol on neointimal hyperplasia.
Results: Egfl7 had potent anti-inflammatory properties including inhibition of NF-κB pathway activation, ICAM-1 expression and neutrophil adhesion to injured endothelium. Within vessels exhibiting neointimal hyperplasia, Egfl7 was expressed in regions lacking ICAM-1 expression. Both cilostazol and bosentan attenuated neointimal hyperplasia in isolation as well as during co-treatment with CNI therapies.
Conclusions: Egfl7 is an endothelial protective signaling protein with anti-inflammatory properties effective against simulated ischemia-reperfusion injury and calcineurin inhibition mediated injury. Cilostazol and Bosentan are pharmacologic strategies demonstrating efficacy against the development of neointimal hyperplasia. These observations provide a novel therapeutic target and strategies that may be relevant to endothelial protection and prevention of cardiac allograft vasculopathy following heart transplantation.
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