Human coronary microvascular effects of cardioplegia-induced stromal-derived factor-1alpha.
BACKGROUND
Stromal-derived factor-1alpha (SDF-1alpha) binds to its specific receptor, CXCR4, and plays an important role in ischemia-induced angiogenesis. Some of the effects of SDF-1alpha 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-1alpha expression, and relationships between SDF-1alpha-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-1alpha and CXCR4 were measured by Western blot and immunohistochemistry, and plasma levels of SDF-1alpha were measured by enzyme-linked immunosorbent assay. Coronary microvessel responses to SDF-1alpha were assessed by videomicroscopy. To further elucidate SDF-1alpha/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-1alpha was elevated after CP/CPB (9.5 +/- 3.5-fold, p = 0.03 versus before CP/CPB). Increases in SDF-1alpha spatially localized to endothelial cells, smooth muscle cells, and myocytes. Plasma levels of SDF-1alpha 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-1alpha induced coronary microvessel contraction after CP/CPB (p = 0.046 versus before CP/CPB), which was blocked by the CXCR4 antagonist. Furthermore, SDF-1alpha 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-1alpha and results in coronary microvessel contraction through MAPK signaling pathways.
Mieno
Shigetoshi
S
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Boodhwani
Munir
M
Ramlawi
Basel
B
Li
Jianyi
J
Feng
Jun
J
Bianchi
Cesario
C
Laham
Roger J
RJ
Li
Jian
J
Sellke
Frank W
FW
D000368:Aged; D002315:Cardiopulmonary Bypass; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000097:blood / Q000502:physiology*; D003331:Coronary Vessels / Q000502:physiology*; D005260:Female; D006324:Heart Arrest, Induced; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D019718:Receptors, CXCR4 / Q000032:analysis / Q000502:physiology*; D014661:Vasoconstriction; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019718:Receptors, CXCR4; D048051:p38 Mitogen-Activated Protein Kinases