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Transgenic activation of the kallikrein‐kinin system inhibits intramyocardial inflammation, endothelial dysfunction, and oxidative stress in experimental diabetic cardiomyopathy
Author(s) -
Tschöpe Carsten,
Walther Thomas,
Escher Felicitas,
Spillmann Frank,
Du Jing,
Altmann Christine,
Schimke Ingolf,
Bader Michael,
SanchezFerrer Carlos F.,
Schultheiss HeinzPeter,
Noutsias And Michel
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4095fje
Subject(s) - diabetic cardiomyopathy , medicine , endocrinology , endothelial dysfunction , oxidative stress , tbars , inflammation , cardiomyopathy , heart failure , lipid peroxidation
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; d P/ d t max ; d P/ d t min ) was accompanied by a significant increment of ICAM‐1 and VCAM‐1 (CAMs) expression, as well as of β 2 ‐leukocyte‐integrins + (CD18 + , CD11a + , CD11b + ) and cytokine (TNF‐α and IL‐1β)‐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, β 2 ‐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, β 2 ‐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.