Riad Alexander, Unger Daniel, Du Jing, Westermann Dirk, Mohr Zarah, Sobirey Meike, Dorenkamp Marc, Schultheiss Heinz-Peter, Tschöpe Carsten
Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
Eur J Pharmacol. 2007 Jan 5;554(1):40-5. doi: 10.1016/j.ejphar.2006.08.065. Epub 2006 Sep 14.
To investigate the influence of p38 mitogen activated kinase (p38MAPK) on the development of diabetic cardiac and endothelial dysfunction, we assessed left ventricular and vascular function as well as inflammatory markers in diabetic rats after chronic pharmacological inhibition of p38MAPK. Diabetes mellitus was induced in rats by a single injection of streptozotocin. Rats were treated with the p38MAPK inhibitor SB 239063 (40 mg/kg/day, p.o.) or vehicle. 48 days after diabetes mellitus-induction, left ventricular function and vascular function were assessed in vivo by TIP-catheter and the autoperfused hindlimb, respectively. Cell adhesion molecules staining was quantified immunohistochemically in the heart and quadriceps muscle, respectively, as well as cardiac phosphorylation of p38MAPK by Western blot analysis. Treated and untreated diabetic groups displayed similar severe hyperglycemia. Left ventricular and endothelial function were impaired in the untreated diabetic group compared to controls (dp/dtmax: -40%, dp/dtmin: +49%, maximal vasodilatation: -57%; P < 0.05) associated with significantly increased cardiac (3-fold) and peripheral cell adhesion molecules staining, respectively. Treatment of diabetic rats with SB 239063 led to a significant reduction of diabetes-induced enhancement of p38MAPK phosphorylation associated with improved left ventricular function (dp/dtmax: +39%, dp/dtmin: +47%; P < 0.05) and peripheral endothelial function (maximal vasodilatation: +71%; P < 0.05) under diabetic conditions. This was associated with reduced cardiac and peripheral inflammation indexed by reduced adhesion molecules content. Pharmacological inhibition of p38MAPK is sufficient to mitigate the development of diabetic cardiac and endothelial dysfunction despite of hyperglycemia. Our data suggest that the anti-inflammatory properties due to p38MAPK inhibition contribute to these beneficial cardiovascular effects.
为了研究p38丝裂原活化蛋白激酶（p38MAPK）对糖尿病性心脏和内皮功能障碍发展的影响，我们在对p38MAPK进行慢性药理抑制后，评估了糖尿病大鼠的左心室和血管功能以及炎症标志物。通过单次注射链脲佐菌素诱导大鼠患糖尿病。大鼠接受p38MAPK抑制剂SB 239063（40 mg/kg/天，口服）或赋形剂治疗。糖尿病诱导48天后，分别通过TIP导管和自灌注后肢在体内评估左心室功能和血管功能。分别通过免疫组织化学法定量心脏和股四头肌中的细胞粘附分子染色，并通过蛋白质印迹分析定量心脏中p38MAPK的磷酸化。治疗组和未治疗的糖尿病组表现出相似的严重高血糖症。与对照组相比，未治疗的糖尿病组左心室和内皮功能受损（dp/dtmax：-40%，dp/dtmin：+49%，最大血管舒张：-57%；P<0.05），分别与心脏（3倍）和外周细胞粘附分子染色显著增加有关。用SB 239063治疗糖尿病大鼠导致糖尿病诱导的p38MAPK磷酸化增强显著降低，同时在糖尿病条件下左心室功能（dp/dtmax：+39%，dp/dtmin：+47%；P<0.05）和外周内皮功能（最大血管舒张：+71%；P<0.05）得到改善。这与通过降低粘附分子含量所反映的心脏和外周炎症减轻有关。尽管存在高血糖症，但对p38MAPK进行药理抑制足以减轻糖尿病性心脏和内皮功能障碍的发展。我们的数据表明，p38MAPK抑制所产生的抗炎特性有助于这些有益的心血管效应。
