Tschöpe Carsten, Walther Thomas, Escher Felicitas, Spillmann Frank, Du Jing, Altmann Christine, Schimke Ingolf, Bader Michael, Sanchez-Ferrer Carlos F, Schultheiss Heinz-Peter, Noutsias Michel
Department of Cardiology and Pneumonology, Charité-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
FASEB J. 2005 Dec;19(14):2057-9. doi: 10.1096/fj.05-4095fje. Epub 2005 Aug 29.
The mechanisms contributing to diabetic cardiomyopathy, as well as the protective pathways of the kallikrein-kinin-system (KKS), are incompletely understood. In a kallikrein-overexpressing rat model of streptozotocin (STZ)-induced diabetic cardiomyopathy, we investigated the involvement of inflammatory pathways, endothelial dysfunction, and oxidative stress. Six weeks after STZ injection, impairment of left ventricular (LV) function parameters measured by a Millar-tip catheter (peak LV systolic pressure; dP/dtmax; dP/dtmin) was accompanied by a significant increment of ICAM-1 and VCAM-1 (CAMs) expression, as well as of beta2-leukocyte-integrins+ (CD18+, CD11a+, CD11b+) and cytokine (TNF-alpha and IL-1beta)-expressing infiltrates in male Sprague-Dawley (SD-STZ) rats compared with normoglycemic littermates. Furthermore, SD-STZ rats demonstrated a significant impairment of endothelium-dependent relaxation evoked by acetylcholine and significantly increased plasma TBARS (plasma thiobarbituric acid reactive substances) levels as a measure of oxidative stress. These diabetic cardiomyopathy-associated alterations were significantly attenuated (P<0.05) in diabetic transgenic rats expressing the human kallikrein 1 (hKLK1) gene with STZ-induced diabetes. CAMs expression, beta2-leukocyte-integrins+, and cytokine-expressing infiltrates correlated significantly with all evaluated LV function parameters. The multiple protective effects of the KKS in experimental diabetic cardiomyopathy comprise the inhibition of intramyocardial inflammation (CAMs expression, beta2-leukocyte-integrins+ infiltration and cytokine expression), an improvement of endothelium-dependent relaxation and the attenuation of oxidative stress. These insights might have therapeutic implications also for human diabetic cardiomyopathy.
导致糖尿病性心肌病的机制以及激肽释放酶-激肽系统（KKS）的保护途径尚未完全明确。在链脲佐菌素（STZ）诱导的糖尿病性心肌病的激肽释放酶过表达大鼠模型中，我们研究了炎症途径、内皮功能障碍和氧化应激的参与情况。STZ注射六周后，与血糖正常的同窝仔鼠相比，雄性Sprague-Dawley（SD-STZ）大鼠通过Millar尖端导管测量的左心室（LV）功能参数受损（LV收缩压峰值；dP/dtmax；dP/dtmin），同时伴有细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1，CAMs）表达显著增加，以及β2-白细胞整合素+（CD18+、CD11a+、CD11b+）和细胞因子（肿瘤坏死因子-α和白细胞介素-1β）表达的浸润增加。此外，SD-STZ大鼠表现出乙酰胆碱诱发的内皮依赖性舒张功能显著受损，并且作为氧化应激指标的血浆硫代巴比妥酸反应性物质（TBARS）水平显著升高。在患有STZ诱导糖尿病的人激肽释放酶1（hKLK1）基因表达的糖尿病转基因大鼠中，这些与糖尿病性心肌病相关的改变显著减轻（P<0.05）。CAMs表达、β2-白细胞整合素+和细胞因子表达的浸润与所有评估的LV功能参数显著相关。KKS在实验性糖尿病性心肌病中的多种保护作用包括抑制心肌内炎症（CAMs表达、β2-白细胞整合素+浸润和细胞因子表达）、改善内皮依赖性舒张以及减轻氧化应激。这些见解可能对人类糖尿病性心肌病也具有治疗意义。
