Human coronary microvascular effects of cardioplegia-induced stromal-derived factor-1α

Background. Stromal-derived factor-1 alpha (SDF-1 alpha) binds to its specific receptor, CXCR4, and plays an important role in ischemia-induced angiogenesis. Some of the effects of SDF-1 alpha are likely due to effects on the microcirculation. Cardioplegia and cardiopulmonary bypass (CP/CPB) activate mitogen-activated protein kinase (MAPK) signaling pathways including p38, ERK1/2, and JNK. The purpose of the present study was to evaluate SDF-1 alpha expression, and relationships between SDF-1 alpha-mediated coronary microvessel response and MAPKs. Methods. The atrial tissue of patients undergoing cardiac surgery was harvested before and after CP/CPB. Protein levels of SDF-1 alpha and CXCR4 were measured by Western blot and immunohistochemistry, and plasma levels of SDF-1 alpha were measured by enzyme-linked immunosorbent assay. Coronary microvessel responses to SDF-1 alpha were assessed by videomicroscopy. To further elucidate SDF-1 alpha/CXCR4 signaling, microvessel responses were evaluated in the presence of CXCR4 antagonist (AMD3100) and MAPK inhibitors, ERK1/2 inhibitor (UO126), p38 inhibitor (SB203580), and JNK inhibitor (ALX-159-600). Results. Myocardial protein expression of SDF-1 alpha was elevated after CP/CPB (9.5 +/- 3.5-fold, p = 0.03 versus before CP/CPB). Increases in SDF-1 alpha spatially localized to endothelial cells, smooth muscle cells, and myocytes. Plasma levels of SDF-1 alpha were increased after CP/CPB (3.2 +/- 2.8 versus 2.8 +/- 1.7 ng/mL, p = 0.03 versus before CP/CPB). Stromal-derived factor-1 alpha induced coronary microvessel contraction after CP/CPB (p = 0.046 versus before CP/CPB), which was blocked by the CXCR4 antagonist. Furthermore, SDF-1 alpha induced microvessel contraction was inhibited by MAPK inhibitors, ERK-1/2 (p = 0.046), p38 (p = 0.049), and JNK inhibition (p = 0.06). Conclusions. These results suggest that CP/CPB induces myocardial expression of SDF-1 alpha and results in coronary microvessel contraction through MAPK signaling pathways.