Human Coronary Microvascular Effects of Cardioplegia-Induced Stromal-Derived Factor-1α

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Abstract

Background.

Stromal-derived factor-1α (SDF-1α) binds to its specific receptor, CXCR4, and plays an important role in ischemia-induced angiogenesis. Some of the effects of SDF-1α 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-1α expression, and relationships between SDF-1α-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-1α and CXCR4 were measured by Western blot and immunohistochemistry, and plasma levels of SDF-1α were measured by enzyme-linked immunosorbent assay. Coronary microvessel responses to SDF-1α were assessed by videomicroscopy. To further elucidate SDF-1α/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-1α was elevated after CP/CPB (9.5 ± 3.5-fold,p= 0.03 versus before CP/CPB). Increases in SDF-1α spatially localized to endothelial cells, smooth muscle cells, and myocytes. Plasma levels of SDF-1α 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-1α induced coronary microvessel contraction after CP/CPB (p= 0.046 versus before CP/CPB), which was blocked by the CXCR4 antagonist. Furthermore, SDF-1α 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-1α and results in coronary microvessel contraction through MAPK signaling pathways.

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