Activation of NF-κB is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes

Purcell, Nicole H.; Tang, Guilin; Yu, Chenfei; Mercurio, Frank; DiDonato, Joseph A.; Lin, Anning

doi:10.1073/pnas.111155798

Cited by 301 publications

(251 citation statements)

References 59 publications

(102 reference statements)

Supporting

Mentioning

234

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, the NF B dimer ratio has been shown to determine the ultimate level of target gene expression (18,22). NF B-mediated gene transcription has been proposed in models of myocardial diseases (3,77,78). Taken together with the previous finding that elevated levels of Myo/V1 are found in failing mammalian hearts (5,6), this study collectively suggests that Myo/V1 might play a significant NF B regulatory role at the transcriptional level during chronic pathophysiological conditions such as human heart failure.…”

Section: Figsupporting

confidence: 57%

Myotrophin/V-1, a Protein Up-regulated in the Failing Human Heart and in Postnatal Cerebellum, Converts NFκB p50-p65 Heterodimers to p50-p50 and p65-p65 Homodimers

Knuefermann¹,

Chen²,

Misra

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Myotrophin/V-1 is a cytosolic protein found at elevated levels in failing human hearts and in postnatal cerebellum. We have previously shown that it disrupts nuclear factor of B (NF B)-DNA complexes in vitro. In this study, we demonstrated that in HeLa cells native myotrophin/V-1 is predominantly present in the cytoplasm and translocates to the nucleus during sustained NF B activation. Three-dimensional alignment studies indicate that myotrophin/V-1 resembles a truncated I B␣ without the signal response domain (SRD) and PEST domains. Co-immunoprecipitation studies reveal that myotrophin/V-1 interacts with NF B proteins in vitro; however, it remains physically associated only with p65 and c-Rel proteins in vivo during NF B activation. In vitro studies indicate that myotrophin/V-1 can promote the formation of p50-p50 homodimers from monomeric p50 proteins and can convert the preformed p50-p65 heterodimers into p50-p50 and p65-p65 homodimers. Furthermore, adenovirus-mediated overexpression of myotrophin/V-1 resulted in elevated levels of both p50-p50 and p65-p65 homodimers exceeding the levels of p50-p65 heterodimers compared with Ad␤gal-infected cells, where the levels of p50-p65 heterodimers exceeded the levels of p50-p50 and p65-p65 homodimers. Thus, overexpression of myotrophin/V-1 during NF B activation resulted in a qualitative shift by quantitatively reducing the level of transactivating heterodimers while elevating the levels of repressive p50-p50 homodimers. Correspondingly, overexpression of myotrophin/V-1 resulted in significantly reduced B-luciferase reporter activity. Because myotrophin/V-1 is found at elevated levels during NF B activation in postnatal cerebellum and in failing human hearts, this study cumulatively suggests that myotrophin/V-1 is a regulatory protein for modulating the levels of activated NF B dimers during this period.

show abstract

Section: Figsupporting

confidence: 57%

Myotrophin/V-1, a Protein Up-regulated in the Failing Human Heart and in Postnatal Cerebellum, Converts NFκB p50-p65 Heterodimers to p50-p50 and p65-p65 Homodimers

Knuefermann¹,

Chen²,

Misra

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Recent studies have suggested that NF-κB signaling seems to be involved in a number of cytokines gene expressions, and development of cardiac hypertrophy in vivo and in vitro conditions (18,26). The exact intracellular mechanisms underlying the activation of cytokines in mice lacking NPRA are not well understood.…”

Section: Discussionmentioning

confidence: 99%

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

2007

View full text Add to dashboard Cite

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.

show abstract

“…In this context, a number of genes altered by HS diet were normalized by PC including the myosin heavy-chain isoform switch characteristic of loaddependent hypertrophy (10,14). Changes in ␣-tropomyosin and in the NF-B pathway, which have been linked with ventricular hypertrophy (31,32), were also positively modified by PC. This is consistent with the finding that 1,25(OH) 2 D 3 significantly blunts the activation of NF-B signaling in vitro (33).…”

Section: Discussionmentioning

confidence: 99%

Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals

Bodyak

Ayus²,

Achinger³

et al. 2007

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

304

250

View full text Add to dashboard Cite

Observations in hemodialysis patients suggest a survival advantage associated with activated vitamin D therapy. Left ventricular (LV) structural and functional abnormalities are strongly linked with hemodialysis mortality. Here, we investigated whether paricalcitol (PC, 19-nor-1,25(OH)2D2), an activated vitamin D compound, attenuates the development of LV abnormalities in the Dahl salt-sensitive (DSS) rat and whether humans demonstrate comparable findings. Compared with DSS rats fed a high-salt (HS) diet (6% NaCl for 6 weeks), HS؉PC was associated with lower heart and lung weights, reduced LV mass, posterior wall thickness and end diastolic pressures, and increased fractional shortening. Blood pressures did not significantly differ between the HS groups. Plasma brain natriuretic peptide levels, and cardiac mRNA expression of brain natriuretic peptide, atrial natriuretic factor, and renin were significantly reduced in the HS؉PC animals. Microarray analyses revealed 45 specific HS genes modified by PC. In a retrospective pilot study of hemodialysis patients, PC-treated subjects demonstrated improved diastolic function and a reduction in LV septal and posterior wall thickness by echocardiography compared with untreated patients. In summary, PC attenuates the development of LV alterations in DSS rats, and these effects should be examined in human clinical trials.cardiac hypertrophy ͉ heart failure ͉ paricalcitol ͉ renal failure T he rate of cardiovascular-related mortality in hemodialysis patients is 10-20 times higher than that observed in the general population (1). Left ventricular hypertrophy (LVH) and diastolic dysfunction are present in Ͼ50% of patients at dialysis initiation, and these abnormalities are strongly linked with dialysis-related mortality (2). Currently, there are no well accepted means to modify cardiac structural and functional alterations in renal-failure patients.We recently demonstrated in observational studies that therapy with activated vitamin D to chronic hemodialysis patients is associated with reduction in cardiovascular-related mortality (3, 4). Conversion of nutritional vitamin D (25(OH)D 3 ) to the hormonally active form of vitamin D (1,25(OH) 2 D 3 ) occurs primarily in the kidney; thus, patients with kidney failure commonly present with altered vitamin D status (5). There is growing evidence that vitamin D either directly or indirectly affects cardiac structure and function. The vitamin D receptor knockout mouse model demonstrates increased cardiac renin expression and marked cardiomyocyte hypertrophy (6), and 1,25(OH) 2 D 3 attenuates cardiomyocyte proliferation (7) and hypertrophy (8) in vitro. Here, we demonstrate that treatment with an activated vitamin D compound attenuates the development of cardiac hypertrophy and dysfunction in a recognized animal model of such abnormalities and that comparable findings are evident in humans.

show abstract

Activation of NF-κB is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes

Cited by 301 publications

References 59 publications

Myotrophin/V-1, a Protein Up-regulated in the Failing Human Heart and in Postnatal Cerebellum, Converts NFκB p50-p65 Heterodimers to p50-p50 and p65-p65 Homodimers

Myotrophin/V-1, a Protein Up-regulated in the Failing Human Heart and in Postnatal Cerebellum, Converts NFκB p50-p65 Heterodimers to p50-p50 and p65-p65 Homodimers

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

Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals

Contact Info

Product

Resources

About