Involvement of Nuclear Factor-κB and Apoptosis Signal-Regulating Kinase 1 in G-Protein–Coupled Receptor Agonist–Induced Cardiomyocyte Hypertrophy

Hirotani, Shinichi; Otsu, Kinya; Nishida, Keiya; Higuchi, Yoshiharu; Morita, Takashi; Nakayama, Hiroyuki; Yamaguchi, Osamu; Mano, Toshiaki; Matsumura, Yasushi; Ueno, Hikaru; Tada, Michihiko; Hori, Masatsugu

doi:10.1161/hc0402.102863

Cited by 343 publications

(290 citation statements)

References 19 publications

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“…This is consistent with an earlier study that showed that hyperglycemia itself enhances oxidative stress. 39 Oxidative stress, which is also activated by an AT 1 R-mediated pathway 40,41 and promotes myocardial fibrosis, 15,42 is likely to be involved in the development of myocardial fibrosis in DM, as shown in this study. Furthermore, we were able to show that there was a positive correlation between the extent of cardiac ACE expression and that of diastolic dysfunction.…”

Section: Impact Of Dm On Diastolic Dysfunction Myocardial Fibrosis Asupporting

confidence: 58%

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

et al. 2009

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Diabetes mellitus (DM) is a major risk factor for heart failure, independent of coronary artery disease or hypertension (HT). Therefore, our study was designed to examine the mechanisms of DM-induced left ventricular (LV) diastolic dysfunction. In this study, we made five different 10-week treatment groups of Dahl salt-sensitive rats as follows: Control; a low-salt (0.5% NaCl) diet, HT; a high-salt (5% NaCl) diet, DM; a low-salt diet with streptozotocin (STZ) injection (30 mg kg À1 i.p.), HT+DM; a highsalt diet with STZ injection, and the Olmesartan group; a high-salt diet with STZ treated with an angiotensin receptor blocker, olmesartan (1 mg kg À1 day À1 ). Cardiac diastolic dysfunction with a preserved systolic function was noted in the HT group, and was most prominently noted in the HT+DM group, characterized by enhanced cardiac fibrosis, whereas the extent of HT and myocardial hypertrophy was comparable between the two groups. Myocardial expressions of collagen III, transforming growth factor-b2, angiotensin-converting enzyme (ACE), angiotensin II type-1 receptor and myocardial oxidative stress (evaluated by 4-hydroxy-2-nonenal-modified protein) were mostly enhanced in the HT+DM group. Importantly, there was a positive correlation between the extent of diastolic dysfunction and that of myocardial ACE expression. All these cardiac abnormalities induced by DM and HT were ameliorated in the olmesartan group. These results indicate that DM accelerates diastolic dysfunction in hypertensive heart disease through activation of the renin-angiotensin system, with subsequent inflammatory and oxidative stresses and myocardial fibrosis, suggesting that an inhibition of the system is effective for the treatment of diastolic dysfunction in this combined disorder.

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Section: Impact Of Dm On Diastolic Dysfunction Myocardial Fibrosis Asupporting

confidence: 58%

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

et al. 2009

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“…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

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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.

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“…Because in other studies interactions between GRK5 and NF-B signaling components (albeit at the protein level) have been demonstrated (14 -17), we looked for the potential of this system that can be activated by PKC to regulate GRK5 expression in myocytes. NF-B activation occurs through IB degradation and subsequent nuclear translocation of the p65 subunit to regulate gene transcription (9,32,33). 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).…”

Section: Discussionmentioning

confidence: 99%

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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Involvement of Nuclear Factor-κB and Apoptosis Signal-Regulating Kinase 1 in G-Protein–Coupled Receptor Agonist–Induced Cardiomyocyte Hypertrophy

Abstract: These data indicate that GPCR agonist-induced cardiac hypertrophy is mediated through NF-kappaB activation via the generation of ROS. ASK1 is involved in GPCR agonist-induced NF-kappaB activation and resulting hypertrophy.

Cited by 343 publications

References 19 publications

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

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

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

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