Cardiac-specific suppression of NF-kappa B signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system

Cardiac-specific suppression of NF-kappa B signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system

Author Thomas, Candice M. Google Scholar
Yong, Qian Chen Google Scholar
Rosa, Rodolfo M. Autor UNIFESP Google Scholar
Seqqat, Rachid Google Scholar
Gopal, Shanthi Google Scholar
Casarini, Dulce E. Autor UNIFESP Google Scholar
Jones, W. Keith Google Scholar
Gupta, Sudhiranjan Google Scholar
Baker, Kenneth M. Google Scholar
Kumar, Rajesh Google Scholar
Institution Texas A&M Hlth Sci Ctr
Baylor Scott & White Hlth
Cent Texas Vet Hlth Care Syst
Universidade Federal de São Paulo (UNIFESP)
Loyola Univ Chicago
Abstract Activation of NF-kappa B signaling in the heart may be protective or deleterious depending on the pathological context. in diabetes, the role of NF-kappa B in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-kappa B modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated I kappa B-alpha in the heart (3M mice), which prevented activation of canonical NF-kappa B signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. in contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. in diabetic WT mice, an increase in the phospholamban/sarco(endo) plasmic reticulum Ca2+-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca2+ handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. in conclusion, these results demonstrate that inhibition of NF-kappa B signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca2+ handling and inhibition of the cardiac renin-angiotensin system.
Keywords nuclear factor-kappa B
renin-angiotensin system
diabetic cardiomyopathy
I kappa B-alpha transgenic mice
Language English
Sponsor National Heart, Lung, and Blood Institute
Grant number National Heart, Lung, and Blood Institute: 5-R01-HL-090817
Date 2014-10-01
Published in American Journal of Physiology-heart and Circulatory Physiology. Bethesda: Amer Physiological Soc, v. 307, n. 7, p. H1036-H1045, 2014.
ISSN 0363-6135 (Sherpa/Romeo, impact factor)
Publisher Amer Physiological Soc
Extent H1036-H1045
Origin http://dx.doi.org/10.1152/ajpheart.00340.2014
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000343239800011
URI http://repositorio.unifesp.br/handle/11600/38241

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