title: Loss of bradykinin signaling does not accelerate the development of cardiac dysfunction in type 1 diabetic akita mice.
abstract: Bradykinin signaling has been proposed to play either protective or deleterious roles in the development of cardiac dysfunction in response to various pathological stimuli. To further define the role of bradykinin signaling in the diabetic heart, we examined cardiac function in mice with genetic ablation of both bradykinin B1 and B2 receptors (B1RB2R(-/-)) in the context of the Akita model of insulin-deficient type 1 diabetes (Ins2(Akita/+)). In 5-month-old diabetic and nondiabetic, wild-type and B1RB2R(-/-) mice, in vivo cardiac contractile function was determined by left-ventricular (LV) catheterization and echocardiography. Reactive oxygen species levels were measured by 2'-7'-dichlorofluorescein diacetate fluorescence. Mitochondrial function and ATP synthesis were determined in saponin-permeabilized cardiac fibers. LV systolic pressure and the peak rate of LV pressure rise and decline were decreased with diabetes but did not deteriorate further with loss of bradykinin signaling. Wall thinning and reduced ejection fractions in Akita mouse hearts were partially attenuated by B1RB2R deficiency, although other parameters of LV function were unaffected. Loss of bradykinin signaling did not increase fibrosis in Ins2(Akita/+) diabetic mouse hearts. Mitochondrial dysfunction was not exacerbated by B1RB2R deficiency, nor was there any additional increase in tissue levels of reactive oxygen species. Thus, loss of bradykinin B2 receptor signaling does not abrogate the previously reported beneficial effect of inhibition of B1 receptor signaling. In conclusion, complete loss of bradykinin expression does not worsen cardiac function or increase myocardial fibrosis in diabetes.
authors.affiliation: Program in Molecular Medicine and Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, Utah 84112, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wende
authors.forename: Jamie
authors.initials: J
authors.lastname: Soto
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Olsen
authors.forename: Karla M P
authors.initials: KM
authors.lastname: Pires
authors.forename: John C
authors.initials: JC
authors.lastname: Schell
authors.forename: Frederic
authors.initials: F
authors.lastname: Larrieu-Lahargue
authors.forename: Sheldon E
authors.initials: SE
authors.lastname: Litwin
authors.forename: Masao
authors.initials: M
authors.lastname: Kakoki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Oliver
authors.initials: O
authors.lastname: Smithies
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000378:metabolism / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006321:Heart / Q000503:physiopathology; D006331:Heart Diseases / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000473:pathology / Q000502:physiology; D009206:Myocardium / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D043783:Receptor, Bradykinin B1 / Q000172:deficiency / Q000235:genetics; D043782:Receptor, Bradykinin B2 / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors
chemical_list: D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D001920:Bradykinin