Inhibition of NF-κB induces regression of cardiac hypertrophy, independent of blood pressure control, in spontaneously hypertensive rats

Gupta, Sudhiranjan; Young, D. R.; Sen, Subha

doi:10.1152/ajpheart.00082.2005

Cited by 76 publications

(69 citation statements)

References 46 publications

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“…We would argue that such genes would be more likely to be those that cause altered heart size in the SHR and act independently of the elevated blood pressure in this strain. For example, we found differential expression of the NF-κB gene in HHR in our study, a finding which has previously been reported in SHR (52). The suggestion by Gupta et al that this particular gene causes cardiac hypertrophy independently of blood pressure is thus supported by our finding that the normotensive HHR has altered expression of this gene (52).…”

Section: Discussionsupporting

confidence: 90%

“…For example, we found differential expression of the NF-κB gene in HHR in our study, a finding which has previously been reported in SHR (52). The suggestion by Gupta et al that this particular gene causes cardiac hypertrophy independently of blood pressure is thus supported by our finding that the normotensive HHR has altered expression of this gene (52). Other genes that we report as differentially expressed between HHR and NHR, and which have also been reported as having altered expression in the SHR include TGF-β1 (53,54), Nppb (brain natriuretic peptide) (55)(56)(57) and Mapk1 (58).…”

Section: Discussionsupporting

confidence: 89%

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Myocardial Gene Expression Associated with Genetic Cardiac Hypertrophy in the Absence of Hypertension

et al. 2008

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

Myocardial Gene Expression Associated with Genetic Cardiac Hypertrophy in the Absence of Hypertension

et al. 2008

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“…It has been described that the inhibition of NF-B reduces LVH in SHRs in a BP-independent manner. 25 Indeed, the antihypertensive drug hydralazine has no effect on cardiac mass or NF-B activity in hypertrophic SHRs. 25 On the contrary, the pharmacological inhibition of NF-B with pyrrolidine dithiocarbamate or the treatment with an angiotensin-converting enzyme inhibitor (captopril) significantly reduces heart size and inhibits NF-B activity.…”

Section: Discussionmentioning

confidence: 99%

Intracardiac Injection of AdGRK5-NT Reduces Left Ventricular Hypertrophy by Inhibiting NF-κB–Dependent Hypertrophic Gene Expression

et al. 2010

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Abstract-Several studies underline the role of the transcription factor NF-B in the development of left cardiac hypertrophy (LVH). We have demonstrated recently that the RGS homology domain within the amino terminus of GRK5 (GRK5-NT) is able to inhibit NF-B transcription activity and its associated phenotypes. The aim of this study was to evaluate the ability of GRK5-NT to regulate LVH through the inhibition of NF-B both in vitro and in vivo. In cardiomyoblasts, GRK5-NT inhibits phenylephrine-induced transcription of both NF-B and atrial natriuretic factor promoters, assessed by luciferase assay, thus confirming a role for this protein in the regulation of cardiomyocyte hypertrophy. In vivo, we explored 2 rat models of LVH, the spontaneously hypertensive rat and the normotensive Wistar Kyoto rat exposed to chronic administration of phenylephrine. Intracardiac injection of an adenovirus encoding for GRK5-NT reduces cardiac mass in spontaneously hypertensive rats and prevents the development of phenylephrineinduced LVH in Wistar Kyoto rats. This associates with inhibition of NF-B signaling (assessed by NF-B levels), transcriptional activity and phenotypes (fibrosis and apoptosis). Such phenomenon is independent from hemodynamic changes, because adenovirus encoding for GRK5-NT did not reduce blood pressure levels in spontaneously hypertensive rats or in Wistar Kyoto rats. In conclusion, our study supports the regulation of LVH based on the GRK5-NT inhibition of the NF-B transduction signaling. (Hypertension. 2010;56:696-704.)Key Words: cardiac hypertrophy Ⅲ intracardiac injection Ⅲ spontaneously hypertensive rats Ⅲ NF-B Ⅲ transcription factors N F-B is an ubiquitously expressed transcription factor that modulates the expression of genes involved in the regulation of cell functions, such as survival, apoptosis, growth, division, innate immunity, differentiation, and cellular responses to stress, hypoxia, and ischemia. 1-4 The classic cellular model in which this factor is studied is the immune system for its central role in cytokine production. 4,5 It has been reported recently that NF-B is relevant in the development of left ventricular hypertrophy (LVH) and remodeling through mechanisms independent from inflammation. NF-B mediates hypertrophic growth of cardiomyocytes in response to G protein-coupled receptor agonists, including norepinephrine, endothelin 1, and angiotensin II. 6,7 Also, NF-B inhibition attenuates LVH in different animal models of disease. 8,9 This evidence suggests that NF-B blockade may be an effective strategy to inhibit LVH and remodeling. The family of G protein-coupled receptor kinases (GRKs) and, in particular GRK2 and GRK5, possesses the ability to bind both NF-B and its inhibitor, IB␣. 10,11 In particular, GRK5, by means of its RGS homology (RH) domain within the amino terminus, interacts with IB␣ leading to the stabilization and accumulation of the IB␣/NF-B complex in the nucleus and, consequently, to the inhibition of NF-B transcriptional activity. 11 This feature of the RH domain of GR...

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“…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).…”

mentioning

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.

161

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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Inhibition of NF-κB induces regression of cardiac hypertrophy, independent of blood pressure control, in spontaneously hypertensive rats

Cited by 76 publications

References 46 publications

Myocardial Gene Expression Associated with Genetic Cardiac Hypertrophy in the Absence of Hypertension

Myocardial Gene Expression Associated with Genetic Cardiac Hypertrophy in the Absence of Hypertension

Intracardiac Injection of AdGRK5-NT Reduces Left Ventricular Hypertrophy by Inhibiting NF-κB–Dependent Hypertrophic Gene Expression

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

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