Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction, and oxidative stress in experimental diabetic cardiomyopathy

Item Type:	Article
Title:	Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction, and oxidative stress in experimental diabetic cardiomyopathy
Creators Name:	Tschoepe, C. and Walther, T. and Escher, F. and Spillmann, F. and Du, J. and Altmann, C. and Schimke, I. and Bader, M. and Sanchez-Ferrer, C.F. and Schultheiss, H.P. and Noutsias, M.
Abstract:	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.
Keywords:	Acetylcholine, Biological Models, CD11a Antigens, CD11b Antigens, CD18 Antigens, Cardiomyopathies, Cell Adhesion, Diastole, Experimental Diabetes Mellitus, Genetically Modified Animals, Heart Ventricles, Inflammation, Intercellular Adhesion Molecule-1, Interleukin-1, Interleukin-2, Kallikrein-Kinin System, Left Ventricular Dysfunction, Myocardium, Oxidative Stress, Pressure, Sprague-Dawley Rats, Streptozocin, Thiobarbituric Acid Reactive Substances, Tissue Kallikreins, Tumor Necrosis Factor-alpha, Vascular Cell Adhesion Molecule-1, Vascular Endothelium, Animals, Rats
Source:	FASEB Journal
ISSN:	0892-6638
Publisher:	Federation of American Societies for Experimental Biology
Volume:	19
Number:	14
Page Range:	2057-2059
Date:	29 August 2005
Official Publication:	https://doi.org/10.1096/fj.05-4095fje
PubMed:	View item in PubMed

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