Abstract 19634: Deletion of Semaphorin 4d Protects Against Myocardial Ischemia-reperfusion Injury in Mice
Semaphorin 4D (Sema4D) is expressed on the surface of many types of cells including platelets and T-cells. We have previously shown that Sema4D can be shed from the surface of activated platelets by the metalloprotease ADAM17 and that deleting Sema4D in mice inhibits platelet function and reduces lipid deposition in the aorta. Here we asked whether loss of Sema4D expression protects heart in an ischemia/reperfusion model in which the LAD is occluded for 45 min and then reperfused for 1 hour. The results show that there was no difference between Sema4D(-/-) and control (WT) mice with respect to heart size or the area at risk for infarction. However, we found a substantial decrease in infarct size when adjusted for either heart size (10.7% versus 30.2%, p<0.01) or area at risk (19.7% versus 64.0%, p<0.01) in the Sema4D(-/-) mice compared to WT. Consistent with this effect, there was also a small, but significant, increase in cardiac function in Sema4D(-/-) mice relative to controls as measured by LVEF (46.9% versus 39.3%, p<0.01) and LVFS (23.5% versus 20.5%, p<0.01) determined 24 hours post-reperfusion. In studies focused on mechanism, we found that the injured areas showed fewer capillary microthrombi in Sema4D(-/-) mice, less formation of circulating platelet:neutrophil aggregates and decreased neutrophil infiltration into heart. Sema4D and two of its receptors, plexin B1 and plexin B2, were detectable in heart tissue. Deletion of Sema4D reduced Rho kinase activation downstream of Sema4D receptors and enhanced Akt phosphorylation, which may lead to less apoptosis during ischemia reperfusion injury as we showed a decreased caspase 3 level in injured heart when Sema4D is absent. Finally, the extent of infarction was unaffected in the myocardial ischemia/reperfusion model when ADAM17 was deleted from hematopoietic cells. These results show that 1) Sema4D contributes to the damage occurring in the setting of ischemia and reperfusion, 2) deleting Sema4D can confer protection in part by reducing neutrophil activation and post-receptor Rho kinase activation in the injured tissue, and 3) although blocking ADAM17 prevented shedding of Sema4D from hematopoietic cells, it did not protect against ischemia/reperfusion injury.
Author Disclosures: L. Zhu: None. X. Liu: None. D. Xu: None. T. Wang: None. Q. Lu: None. L. Ren: None. A. Kumannogoh: None. L. Brass: None.
- © 2014 by American Heart Association, Inc.