Involvement of the NF-κB/Matrix Metalloproteinase Pathway in Cardiac Fibrosis of Mice Lacking Guanylyl Cyclase/Natriuretic Peptide Receptor A

Vellaichamy, Elangovan; Khurana, Madan Lal; Fink, Jude; Pandey, Kailash N.

doi:10.1074/jbc.m411373200

Cited by 92 publications

(167 citation statements)

References 58 publications

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“…Electrophoretic mobility shift assay (EMSA) was performed as described previously (31). Double-stranded oligonucleotides containing the consensus-binding site for NF-κB were endlabeled using [γ-32 p]ATP and T4 polynucleotide kinase.…”

Section: Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

Enhanced activation of pro-inflammatory cytokines in mice lacking natriuretic peptide receptor-A

2007

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Natriuretic peptide receptor-A (NPRA) is the principal receptor for the cardiac hormones ANP and BNP. Mice lacking NPRA develop progressive cardiac hypertrophy and congestive heart failure. However, the mechanisms responsible for hypertrophic growth in the absence of NPRA signaling are not yet known. In the present study, we determined whether deficiency of NPRA/cGMP signaling alters the cardiac pro-inflammatory cytokines gene expression in Npr1 (coding for NPRA) geneknockout (Npr1 −/− ) mice exhibiting cardiac hypertrophy and fibrosis as compared with control wildtype (Npr1 +/+ ) mice. A significant up-regulation of cytokine genes such as TNF-α (5-fold), IL-6 (3-fold) and TGF-β1 (4-fold) were observed in mutant mice hearts lacking NPRA as compared with the age-matched wild-type mice. In parallel, NF-κB binding activity was almost 5-fold greater in the nuclear extract of Npr1 −/− mutant mice hearts as compared with wild-type Npr1 +/+ mice hearts. Guanylyl cyclase (GC) activity and cGMP levels were drastically reduced by 10-fold and 6-fold, respectively, in ventricular tissues of mutant mice hearts relative to wild-type controls. The present findings provide direct evidence that ablation of NPRA/cGMP signaling activates inflammatory cytokines, probably via NF-κB mediated signaling pathway, and is associated with hypertrophic growth of null mutant mice hearts.

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Section: Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

Enhanced activation of pro-inflammatory cytokines in mice lacking natriuretic peptide receptor-A

2007

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“…Cardiac fibroblasts (CF) are recognized as the major cell type responsible for the homeostatic maintenance of the extracellular matrix (ECM) (Vellaichamy et al 2005). Cardiac fibroblasts are activated after myocardial infarctions or diseases and contribute to wound healing of the apoptotic or necrotic tissue where a stepwise remodelling of the ECM takes place (Colston et A C C E P T E D M A N U S C R I P T -6 -al.…”

Section: Introductionmentioning

confidence: 99%

Preconditioning with Maillard reaction products improves antioxidant defence leading to increased stress tolerance in cardiac cells

Ruhs

Naß

Bartling

et al. 2010

Experimental Gerontology

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International audienceAdvanced glycation end products (AGEs) are considered as biomarkers of ageing and are associated with several degenerative diseases. Besides endogenous formation, significant amounts of AGEs are taken up with food. Although nutritional AGEs are considered as undesirable, proinflammatory agents, they may also enclose potentially beneficial antioxidants. We used rodent cardiac cells to evaluate if food AGEs, present in bread crust, can modify the cellular antioxidant defence. Mice were fed with bread crust containing diet to prove the in-vivo relevance for the heart. In mouse cardiac fibroblasts, bread crust extract induced a moderate elevation of ROS production causing an activation of p42/p44, p38 and NF-κB, followed by increased expression of antioxidative enzymes. Preconditioning studies demonstrated that this was sufficient to protect cardiac fibroblasts and rat adult cardiac myocytes against severe oxidative stress. Furthermore, mice, fed a bread crust containing diet, exhibited a similarly improved cardiac expression of antioxidative defence genes. The consumption of AGEs can therefore contribute to an improved antioxidant status of the heart, thus exhibiting cardioprotective effects in case of severe oxidative stress as in ischemia reperfusion injury. Also, these data show that the exclusive interpretation of circulating AGEs as pathophysiological biomarkers of ageing might be misleading

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“…ANP and BNP are released from the heart into the circulation and elicit natriuretic, diuretic, vasorelaxant, and antiproliferative responses, all directed to reduce blood pressure and blood volume (11,18,38,65). Distinct natriuretic peptide receptors have been identified and characterized by molecular cloning (51,56), which includes natriuretic peptide receptor -A, -B, and -C, also designated, respectively, as NPRA, NPRB, and NPRC (18,37).…”

mentioning

confidence: 99%

“…Distinct natriuretic peptide receptors have been identified and characterized by molecular cloning (51,56), which includes natriuretic peptide receptor -A, -B, and -C, also designated, respectively, as NPRA, NPRB, and NPRC (18,37). Both ANP and BNP bind to guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA), which is considered to be the principal natriuretic peptide receptor that synthesizes intracellular second messenger cGMP (15,50,65). Mice carrying targeted disruption of the Npr1 gene (encoding for GC-A/NPRA) exhibit hypertension, congestive heart failure, reduced kidney function, and altered plasma renin and angiotensin II (ANG II) levels (47,58,59,65).…”

mentioning

confidence: 99%

Activation of IKK/NF-κB provokes renal inflammatory responses in guanylyl cyclase/natriuretic peptide receptor-A gene-knockout mice

Das

Periyasamy

Pandey

2012

Physiological Genomics

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The present study was aimed at determining the consequences of the disruption of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene ( Npr1) on proinflammatory responses of nuclear factor kappa B, inhibitory kappa B kinase, and inhibitory kappa B alpha (NF-κB, IKK, IκBα) in the kidneys of mutant mice. The results showed that the disruption of Npr1 enhanced the renal NF-κB binding activity by 3.8-fold in 0-copy (−/−) mice compared with 2-copy (+/+) mice. In parallel, IKK activity and IκBα protein phosphorylation were increased by 8- and 11-fold, respectively, in the kidneys of 0-copy mice compared with wild-type mice. Interestingly, IκBα was reduced by 80% and the expression of proinflammatory cytokines and renal fibrosis were significantly enhanced in 0-copy mice than 2-copy mice. Treatment of 0-copy mice with NF-κB inhibitors andrographolide, pyrrolidine dithiocarbamate, and etanercept showed a substantial reduction in renal fibrosis, attenuation of proinflammatory cytokines gene expression, and significantly reduced IKK activity and IkBα phosphorylation. These findings indicate that the systemic disruption of Npr1 activates the renal NF-κB pathways in 0-copy mice, which transactivates the expression of various proinflammatory cytokines to initiate renal remodeling; however, inhibition of NF-κB pathway repairs the abnormal renal pathology in mutant mice.

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Involvement of the NF-κB/Matrix Metalloproteinase Pathway in Cardiac Fibrosis of Mice Lacking Guanylyl Cyclase/Natriuretic Peptide Receptor A

Cited by 92 publications

References 58 publications

Enhanced activation of pro-inflammatory cytokines in mice lacking natriuretic peptide receptor-A

Enhanced activation of pro-inflammatory cytokines in mice lacking natriuretic peptide receptor-A

Preconditioning with Maillard reaction products improves antioxidant defence leading to increased stress tolerance in cardiac cells

Activation of IKK/NF-κB provokes renal inflammatory responses in guanylyl cyclase/natriuretic peptide receptor-A gene-knockout mice

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