Khan Tanveer A, Bianchi Cesario, Ruel Marc, Voisine Pierre, Li Jianyi, Liddicoat John R, Sellke Frank W
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Circulation. 2003 Sep 9;108 Suppl 1:II348-53. doi: 10.1161/01.cir.0000087652.93751.0e.
Cardioplegia-cardiopulmonary bypass (C/CPB) is associated with coronary microcirculatory dysfunction. Regulation of the microcirculation includes myogenic tone. Mitogen-activated protein kinases (MAPK) have been implicated in coronary vasomotor function. We hypothesized that vasomotor dysfunction of the coronary microcirculation is mediated in part by alterations in extracellular signal regulated kinase 1/2 (ERK1/2) activity following C/CPB in humans.
Atrial myocardium was harvested from patients (n=15) before and after blood cardioplegia and short-term reperfusion under conditions of CPB. Myogenic tone of coronary arterioles was measured by videomicroscopy. Microvessel tone was determined post-C/CPB and after PD98059, a MAPK/ERK kinase 1/2 (MEK1/2) inhibitor. MAPK phosphatase-1 (MKP-1) and activated ERK1/2 were measured by Western blot. MKP-1 gene expression was determined by Northern blot. In situ hybridization and immunohistochemistry were used to localize myocardial MKP-1 and activated ERK1/2, respectively. Myogenic tone was reduced in coronary arterioles post-C/CPB (-10.5+/-0.9%, P<0.01 versus control/pre-C/CPB, n=5). Myogenic tone was decreased in coronary microvessels after 30 micromol/L (n=5) and 50 micromol/L (n=5) PD98059 treatment (-11.0+/-0.8% and -14.6+/-2.0%, respectively, both P<0.01 versus control/pre-C/CPB). Myocardial levels of activated ERK1/2 were reduced post-C/CPB (0.6+/-0.1, post/pre-C/CPB ratio, P<0.05, n=5) while MKP-1 levels increased (4.2+/-0.6, post/pre-C/CPB ratio, P<0.05, n=5). Myocardial MKP-1 gene expression increased post-C/CPB (3.0+/-0.8, post/pre-C/CPB ratio, P<0.05, n=5). MKP-1 and activated ERK1/2 localized to coronary arterioles in myocardial sections.
Coronary myogenic tone is dependent on ERK1/2 and decreased after C/CPB. C/CPB reduces levels of activated ERK1/2, potentially by increased levels of MKP-1. The ERK1/2 signal transduction pathway in part mediates coronary microvascular dysfunction after C/CPB in humans.
心脏停搏液 - 体外循环（C/CPB）与冠状动脉微循环功能障碍有关。微循环的调节包括肌源性张力。丝裂原活化蛋白激酶（MAPK）与冠状动脉血管舒缩功能有关。我们假设，在人类C/CPB后，冠状动脉微循环的血管舒缩功能障碍部分是由细胞外信号调节激酶1/2（ERK1/2）活性的改变介导的。
在体外循环条件下，于血液心脏停搏液灌注前及短期再灌注后，从患者（n = 15）获取心房心肌。通过视频显微镜测量冠状动脉小动脉的肌源性张力。在C/CPB后以及给予MAPK/ERK激酶1/2（MEK1/2）抑制剂PD98059后，测定微血管张力。通过蛋白质免疫印迹法测量MAPK磷酸酶 - 1（MKP - 1）和活化的ERK1/2。通过Northern印迹法测定MKP - 1基因表达。分别采用原位杂交和免疫组织化学法对心肌MKP - 1和活化的ERK1/2进行定位。C/CPB后冠状动脉小动脉的肌源性张力降低（-10.5±0.9%，与对照组/C/CPB前相比P<0.01，n = 5）。给予30 μmol/L（n = 5）和50 μmol/L（n = 5）的PD98059后，冠状动脉微血管的肌源性张力降低（分别为-11.0±0.8%和-14.6±2.0%，两者与对照组/C/CPB前相比P均<0.01）。C/CPB后心肌中活化的ERK1/2水平降低（0.6±0.1，C/CPB后与C/CPB前的比值，P<0.05，n = 5），而MKP - 1水平升高（4.2±0.6，C/CPB后与C/CPB前的比值，P<0.05，n = 5）。C/CPB后心肌MKP - 1基因表达增加（3.0±0.8，C/CPB后与C/CPB前的比值，P<0.05，n = 5）。在心肌切片中，MKP - 1和活化的ERK1/2定位于冠状动脉小动脉。
冠状动脉肌源性张力依赖于ERK1/2，且在C/CPB后降低。C/CPB可能通过增加MKP - 1水平降低活化的ERK1/2水平。ERK1/2信号转导通路部分介导了人类C/CPB后的冠状动脉微血管功能障碍。
