title: Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system.
abstract: Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB 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 Ca(2+)-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca(2+) 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-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca(2+) handling and inhibition of the cardiac renin-angiotensin system.
authors.affiliation: Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas;
authors.forename: Candice M
authors.initials: CM
authors.lastname: Thomas
authors.affiliation: Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas;
authors.forename: Qian Chen
authors.initials: QC
authors.lastname: Yong
authors.affiliation: Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil; and.
authors.forename: Rodolfo M
authors.initials: RM
authors.lastname: Rosa
authors.affiliation: Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas;
authors.forename: Rachid
authors.initials: R
authors.lastname: Seqqat
authors.affiliation: Central Texas Veterans Health Care System, Temple, Texas;
authors.forename: Shanthi
authors.initials: S
authors.lastname: Gopal
authors.affiliation: Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil; and.
authors.forename: Dulce E
authors.initials: DE
authors.lastname: Casarini
authors.affiliation: Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, Illinois.
authors.forename: W Keith
authors.initials: WK
authors.lastname: Jones
authors.affiliation: Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas;
authors.forename: Sudhiranjan
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas;
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Baker
authors.affiliation: Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas; kumar@medicine.tamhsc.edu.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D012084:Renin-Angiotensin System; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D016328:NF-kappa B; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
keywords: IκB-α transgenic mice; diabetic cardiomyopathy; nuclear factor-κB; renin-angiotensin system
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