Butler Karyn L, Huffman Lynn C, Koch Sheryl E, Hahn Harvey S, Gwathmey Judith K
Department of Surgery, University of Cincinnati, Cincinnati, OH, USA.
Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H797-803. doi: 10.1152/ajpheart.01334.2005. Epub 2006 Mar 24.
The JAK-STAT pathway is activated in the early and late phases of ischemic preconditioning (IPC) in normal myocardium. The role of this pathway and the efficacy of IPC in hypertrophied hearts remain largely unknown. We hypothesized that phosphorylated STAT-3 (pSTAT-3) is necessary for effective IPC in pressure-overload hypertrophy. Male Sprague-Dawley rats 8 wk after thoracic aortic constriction (TAC) or sham operation underwent echocardiography and Langendorff perfusion. Randomized hearts were subjected to 30 min of global ischemia and 120 min of reperfusion with or without IPC in the presence or absence of the JAK-2 inhibitor AG-490 (AG). Functional recovery and STAT activation were assessed. TAC rats had a 31% increase in left ventricular mass (1,347 +/- 58 vs. 1,028 +/- 43 mg, TAC vs. sham, P < 0.001), increased anterior and posterior wall thickness but no difference in ejection fraction compared with sham-operated rats. In TAC, IPC improved end-reperfusion maximum first derivative of developed pressure (+dP/dt(max); 4,648 +/- 309 vs. 2,737 +/- 343 mmHg/s, IPC vs. non-IPC, P < 0.05) and minimum -dP/dt (-dP/dt(min); -2,239 +/- 205 vs. -1,215 +/- 149 mmHg/s, IPC vs. non-IPC, P < 0.05). IPC increased nuclear pSTAT-1 and pSTAT-3 in sham-operated rats but only pSTAT-3 in TAC. AG in TAC significantly attenuated +dP/dt(max) (4,648 +/- 309 vs. 3,241 +/- 420 mmHg/s, IPC vs. IPC + AG, P < 0.05) and -dP/dt(min) (-2,239 +/- 205 vs. -1,323 +/- 85 mmHg/s, IPC vs. IPC + AG, P < 0.05) and decreased only nuclear pSTAT-3. In myocardial hypertrophy, JAK-STAT signaling is important in IPC and exhibits a pattern of STAT activation distinct from nonhypertrophied myocardium. Limiting STAT-3 activation attenuates the efficacy of IPC in hypertrophy.
在正常心肌缺血预处理（IPC）的早期和晚期阶段，JAK-STAT信号通路被激活。该信号通路的作用以及IPC在肥厚心肌中的疗效在很大程度上仍不清楚。我们假设磷酸化的STAT-3（pSTAT-3）对于压力超负荷肥大时有效的IPC是必需的。对雄性Sprague-Dawley大鼠进行胸主动脉缩窄（TAC）或假手术8周后，进行超声心动图检查和Langendorff灌注。随机选取心脏，在有或没有JAK-2抑制剂AG-490（AG）存在的情况下，进行30分钟的全心缺血和120分钟的再灌注，有或没有IPC。评估功能恢复和STAT激活情况。TAC大鼠的左心室质量增加了31%（1347±58 vs. 1028±43 mg，TAC组vs.假手术组，P<0.001），与假手术大鼠相比，前壁和后壁厚度增加，但射血分数无差异。在TAC组中，IPC改善了再灌注末期最大压力上升速率（+dP/dt(max)；4648±309 vs. 2737±343 mmHg/s，IPC组vs.非IPC组，P<0.05）和最小压力下降速率（-dP/dt(min)；-2239±205 vs. -1215±149 mmHg/s，IPC组vs.非IPC组，P<0.05）。IPC增加了假手术大鼠的细胞核pSTAT-1和pSTAT-3，但在TAC大鼠中仅增加了pSTAT-3。TAC组中的AG显著减弱了+dP/dt(max)（4648±309 vs. 3241±420 mmHg/s，IPC组vs. IPC+AG组，P<0.05）和-dP/dt(min)（-2239±205 vs. -1323±85 mmHg/s，IPC组vs. IPC+AG组，P<0.05），并且仅降低了细胞核pSTAT-3。在心肌肥大中，JAK-STAT信号传导在IPC中起重要作用，并且表现出与非肥大心肌不同的STAT激活模式。限制STAT-3激活会减弱IPC在肥大中的疗效。
