Kompa A R, See F, Lewis D A, Adrahtas A, Cantwell D M, Wang B H, Krum H
Department of Epidemiology and Preventive Medicine, Alfred Hospital, Central and Eastern Clinical School, Monash University, Commercial Rd., Prahran, Victoria, Australia.
J Pharmacol Exp Ther. 2008 Jun;325(3):741-50. doi: 10.1124/jpet.107.133546. Epub 2008 Mar 11.
p38 mitogen-activated protein kinase (p38 MAPK) inhibition exerts beneficial effects on left ventricular (LV) remodeling and dysfunction. p38 MAPK activity is transiently increased soon after myocardial infarction (MI), suggesting brief inhibition may afford the same benefit as long-term inhibition. We examined chronic 12-week p38 MAPK inhibition compared with short-term (7-day) inhibition, and then we discontinued inhibition after MI. Post-MI rats at day 7 received either vehicle, 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1-ol (RWJ67657; RWJ) for 12 weeks (long term; LT-RWJ), RWJ for 1 week and discontinued for 11 weeks (1-week RWJ), or continuous ramipril for 12 weeks. In separate groups of animals, 24 h after MI, vehicle or RWJ was administered for 7 days. Cardiac function was assessed by echocardiography and hemodynamic measurements. Percentage of fractional shortening improved after LT-RWJ and ramipril, but not after 1-week RWJ treatment. Likewise, LV contractility and maximal first derivative of left ventricular pressure (dP/dt(max)) was improved (12.5 and 14.4%) and LV end diastolic pressure (LVEDP) was reduced (49.4 and 54.6%) with both treatments. Functional outcomes were accompanied by regression of interstitial collagen I and alpha-smooth muscle actin expression in LV noninfarct, border, and infarct regions with LT-RWJ and ramipril treatment. Hypertrophy was reduced in noninfarct (18.3 and 12.2%) and border regions (16.3 and 12.0%) with both treatments, respectively. Animals receiving RWJ 24 h after MI for 7 days showed similar improvements in fractional shortening, dP/dt(max), LVEDP, including reduced fibrosis and hypertrophy. In vitro experiments confirmed a dose-dependent reduction in hypertrophy, with RWJ following tumor necrosis factor-alpha stimulation. Continuous but not short-term p38 MAPK blockade attenuates post-MI remodeling, which is associated with functional benefits on the myocardium.
p38丝裂原活化蛋白激酶（p38 MAPK）抑制对左心室（LV）重构和功能障碍具有有益作用。心肌梗死（MI）后不久，p38 MAPK活性会短暂升高，这表明短暂抑制可能与长期抑制具有相同的益处。我们比较了慢性12周p38 MAPK抑制与短期（7天）抑制的效果，然后在MI后停止抑制。MI后第7天的大鼠分别接受溶剂、4-[4-(4-氟苯基)-1-(3-苯基丙基)-5-(4-吡啶基)-1H-咪唑-2-基]-3-丁炔-1-醇（RWJ67657；RWJ）持续12周（长期；LT-RWJ）、RWJ治疗1周后停药11周（1周RWJ）或连续服用雷米普利12周。在另一组动物中，MI后24小时给予溶剂或RWJ，持续7天。通过超声心动图和血流动力学测量评估心脏功能。LT-RWJ和雷米普利治疗后，缩短分数百分比有所改善，但1周RWJ治疗后未改善。同样，两种治疗均使LV收缩力和左心室压力的最大一阶导数（dP/dt(max)）提高（分别为12.5%和14.4%），左心室舒张末期压力（LVEDP）降低（分别为49.4%和54.6%）。功能改善伴随着LT-RWJ和雷米普利治疗后LV非梗死区、边缘区和梗死区间质I型胶原蛋白和α-平滑肌肌动蛋白表达的消退。两种治疗分别使非梗死区（分别为18.3%和12.2%）和边缘区（分别为16.3%和12.0%）的肥大减轻。MI后24小时接受RWJ治疗7天的动物在缩短分数、dP/dt(max)、LVEDP方面有类似改善，包括纤维化和肥大减轻。体外实验证实，在肿瘤坏死因子-α刺激后，RWJ可使肥大呈剂量依赖性降低。持续而非短期的p38 MAPK阻断可减轻MI后的重构，这与对心肌的功能益处相关。
