Requirement of Nuclear Factor-κB in Angiotensin II– and Isoproterenol-Induced Cardiac Hypertrophy In Vivo

Freund, Christian; Schmidt‐Ullrich, Ruth; Baurand, Anthony; Dunger, Sandra; Schneider, Wolfgang; Löser, Peter; El-Jamali, Amina; Dietz, Rainer; Scheidereit, Claus; Bergmann, Martin

doi:10.1161/01.cir.0000164237.58200.5a

Cited by 168 publications

(152 citation statements)

References 32 publications

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“…NF-B has been implicated in cardiac hypertrophy, and the best evidence is from a transgenic mouse model with cardiac-specific expression of a mutant IB␣ that acts as a super-repressor of NF-B (30, 31). The expression of this mutant attenuated hypertrophic phenotypes induced by angiotensin II or isoproterenol infusion as well as aortic banding (34,35). The fetal gene program was also abrogated in this model and therefore, irrespective of whether these two molecules can interact at the protein level in the cytoplasm (14 -17), NF-B and GRK5 activity in the heart may lead to inter-related or parallel hypertrophic gene transcriptional paths.…”

Section: Discussionmentioning

confidence: 92%

Involvement of Nuclear Factor κB (NF-κB) Signaling Pathway in Regulation of Cardiac G Protein-coupled Receptor Kinase 5 (GRK5) Expression

Islam

Koch²

2012

Journal of Biological Chemistry

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Background: GRK5 up-regulation and NF-B activation have been shown to be associated with heart disease. Results: NF-B activation in cardiomyocytes promotes stress-induced GRK5 up-regulation. Conclusion: NF-B activation by hypertrophic stimuli/ROS leads to increased binding of NF-B (p50/p65) to the GRK5 promoter, thereby enhancing myocardial GRK5 expression. Significance: NF-B regulation of GRK5 in myocytes may translate to the significant expression changes seen in heart disease.

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Section: Discussionmentioning

confidence: 92%

Involvement of Nuclear Factor κB (NF-κB) Signaling Pathway in Regulation of Cardiac G Protein-coupled Receptor Kinase 5 (GRK5) Expression

Islam

Koch²

2012

Journal of Biological Chemistry

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“…Diabetic hyperglycemia leads to overproduction of ROS, leading to NF‐κB upregulation, in turn promoting the transcription of proinflammatory genes 33, 34. Together, NF‐κB‐mediated vascular inflammation, oxidative stress, vascular and myocardial dysfunction in diabetes mellitus play a pivotal role in the genesis of AF.…”

Section: Discussionmentioning

confidence: 99%

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Yang

Zhao

Qiu

et al. 2018

JAHA

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BackgroundThere are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes.Methods and ResultsNinety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol‐treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. ICaL was measured from isolated left atrial cardiomyocytes using voltage‐clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca2+ handling protein expression was analyzed by Western blotting. Mitochondrial‐related proteins were analyzed as markers of mitochondrial function. Compared with the control group, rabbits with DM showed left ventricular hypertrophy, increased atrial interstitial fibrosis, oxidative stress and fibrosis markers, ICaL and intracellular calcium transient, and atrial fibrillation inducibility. These abnormalities were alleviated by allopurinol treatment.ConclusionsAllopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM‐related increases in oxidative stress.

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“…Previous studies have established that NF-κB is required for cardiac hypertrophy, but is dispensable for normal heart structure and function (8,10,11,27). Our finding that activation of IKK/NF-κB in the heart primarily induces cardiomyocyte atrophy rather than hypertrophy is not necessarily a contradiction to these studies, as the biological function of IKK/NF-κB may depend on the strength of activation and/or on context, and on the component of the IKK/NF-κB system that is manipulated.…”

Section: Role Of Chemokines Cytokines Adhesion Molecules and Myd88mentioning

confidence: 99%

“…The function of IKK/NF-κB during ischemia/reperfusion injury, myocardial infarction, and subsequent remodeling processes is controversial (1,2). As to myocyte growth, IKK/NF-κB activation in vivo is required for certain forms of hypertrophy (8)(9)(10)(11), but not for others (6,7).…”

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confidence: 99%

Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure

Maier

Schips²,

Wietelmann³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

117

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Inflammation is a major factor in heart disease. IκB kinase (IKK) and its downstream target NF-κB are regulators of inflammation and are activated in cardiac disorders, but their precise contributions and targets are unclear. We analyzed IKK/NF-κB function in the heart by a gain-of-function approach, generating an inducible transgenic mouse model with cardiomyocyte-specific expression of constitutively active IKK2. In adult animals, IKK2 activation led to inflammatory dilated cardiomyopathy and heart failure. Transgenic hearts showed infiltration with CD11b + cells, fibrosis, fetal reprogramming, and atrophy of myocytes with strong constitutively active IKK2 expression. Upon transgene inactivation, the disease was reversible even at an advanced stage. IKK-induced cardiomyopathy was dependent on NF-κB activation, as in vivo expression of IκBα superrepressor, an inhibitor of NF-κB, prevented the development of disease. Gene expression and proteomic analyses revealed enhanced expression of inflammatory cytokines, and an IFN type I signature with activation of the IFN-stimulated gene 15 (ISG15) pathway. In that respect, IKK-induced cardiomyopathy resembled Coxsackievirus-induced myocarditis, during which the NF-κB and ISG15 pathways were also activated. Vice versa, in cardiomyocytes lacking the regulatory subunit of IKK (IKKγ/NEMO), the induction of ISG15 was attenuated. We conclude that IKK/NF-κB activation in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure by inducing an excessive inflammatory response and myocyte atrophy.transcription factors | transgenic mice

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Requirement of Nuclear Factor-κB in Angiotensin II– and Isoproterenol-Induced Cardiac Hypertrophy In Vivo

Cited by 168 publications

References 32 publications

Involvement of Nuclear Factor κB (NF-κB) Signaling Pathway in Regulation of Cardiac G Protein-coupled Receptor Kinase 5 (GRK5) Expression

Involvement of Nuclear Factor κB (NF-κB) Signaling Pathway in Regulation of Cardiac G Protein-coupled Receptor Kinase 5 (GRK5) Expression

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure

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