Schwertz Hansjörg, Carter Justin M, Abdudureheman Mulati, Russ Martin, Buerke Ute, Schlitt Axel, Müller-Werdan Ursula, Prondzinsky Roland, Werdan Karl, Buerke Michael
Department of Internal Medicine III, Martin-Luther-University, Halle-Wittenberg, Halle/Saale, Germany.
Proteomics. 2007 Dec;7(24):4579-88. doi: 10.1002/pmic.200700734.
Myocardial ischemia (MI) and reperfusion (R) results in activation of the p38 MAP kinase pathway. This pathway phosphorylates transcription factors and cytoplasmic proteins leading to expression of adhesion molecules and cytokines, increased neutrophil activation, and finally, myocardial necrosis and apoptosis. We studied the effects of a p38 MAP kinase inhibitor, PD169316, on cardioprotection, protein expression, and tyrosine phosphorylation, in a rabbit model of 1 h of (MI) and 3 h of (R). PD169316 administered just before (R) significantly reduced myocardial neutrophil accumulation, necrosis area (28.4 +/- 7.9% vs. 56.4 +/- 7.9% necrosis/AAR), and CK release compared to a vehicle treated group (p<0.05). We found several proteins altered in expression following MI + R alone or with p38 inhibition including myofilament proteins, energetics proteins, heat shock proteins, and the mitochondrial porin VDAC-1. p38 MAPK inhibition significantly reduced the phosphorylation of VDAC-1 which is a known mitochondrial regulator of cell survival. Thus, p38 MAP kinase inhibition with PD169316 is cardioprotective, reduces neutrophil activation, and controls protein expression and phosphorylation in MI and reperfusion.
心肌缺血（MI）和再灌注（R）会导致p38丝裂原活化蛋白激酶（MAPK）信号通路的激活。该信号通路使转录因子和细胞质蛋白磷酸化，从而导致黏附分子和细胞因子的表达增加、中性粒细胞激活增强，最终导致心肌坏死和凋亡。我们在兔心肌缺血1小时及再灌注3小时的模型中，研究了p38 MAPK抑制剂PD169316对心脏保护、蛋白表达及酪氨酸磷酸化的影响。与给予赋形剂处理的组相比，在再灌注前给予PD169316可显著减少心肌中性粒细胞聚集、坏死面积（坏死面积/梗死相关面积分别为28.4±7.9% 与56.4±7.9%）以及肌酸激酶（CK）释放（p<0.05）。我们发现，单独的心肌缺血再灌注或p38抑制后，包括肌丝蛋白、能量代谢蛋白、热休克蛋白及线粒体孔蛋白VDAC-1在内的几种蛋白的表达发生了改变。p38 MAPK抑制可显著降低VDAC-1的磷酸化，VDAC-1是已知的细胞存活线粒体调节因子。因此，用PD169316抑制p38 MAPK具有心脏保护作用，可减少中性粒细胞激活，并可调控心肌缺血再灌注时的蛋白表达及磷酸化。
