title: Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy.
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.
authors.affiliation: Department of Cardiology and Pneumonology, Charité-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany. ctschoepe@yahoo.com
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.forename: Felicitas
authors.initials: F
authors.lastname: Escher
authors.forename: Frank
authors.initials: F
authors.lastname: Spillmann
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.forename: Christine
authors.initials: C
authors.lastname: Altmann
authors.forename: Ingolf
authors.initials: I
authors.lastname: Schimke
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Sanchez-Ferrer
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Michel
authors.initials: M
authors.lastname: Noutsias
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D040881:CD11a Antigen / Q000096:biosynthesis; D039481:CD11b Antigen / Q000096:biosynthesis; D018821:CD18 Antigens / Q000096:biosynthesis / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics*; D002448:Cell Adhesion; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D003971:Diastole; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000378:metabolism; D016234:Kallikrein-Kinin System / Q000235:genetics* / Q000502:physiology*; D008954:Models, Biological; D009206:Myocardium / Q000473:pathology*; D018384:Oxidative Stress; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000494:pharmacology; D017392:Thiobarbituric Acid Reactive Substances; D020840:Tissue Kallikreins / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D018487:Ventricular Dysfunction, Left
chemical_list: D040881:CD11a Antigen; D039481:CD11b Antigen; D018821:CD18 Antigens; D007375:Interleukin-1; D007376:Interleukin-2; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D013311:Streptozocin; D020840:Tissue Kallikreins; D000109:Acetylcholine