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Munir Boodhwani
Basel Ramlawi
Frank W. Sellke
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Ann Thorac Surg 2006;82:657-663
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Human Coronary Microvascular Effects of Cardioplegia-Induced Stromal-Derived Factor-1{alpha}

Shigetoshi Mieno, MDa, Munir Boodhwani, MDa, Basel Ramlawi, MDa, Jianyi Li, MB, MSa, Jun Feng, MD, PhDa, Cesario Bianchi, MD, PhDa, Roger J. Laham, MDa, Jian Li, MD, PhDb, Frank W. Sellke, MDa,*

a Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts
b Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Accepted for publication March 15, 2006.

* Address correspondence to Dr Sellke, Division of Cardiothoracic Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, 110 Francis St, Suite 2A, Boston, MA 02215. (Email: fsellke{at}bidmc.harvard.edu).

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.






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