Nuclear factor-κB signaling contributes to severe, but not moderate, angiotensin II-induced left ventricular remodeling

Balázs Sármán, R. Skoumal, Hanna Leskinen, Jaana Rysä, Mika Ilves, Ylermi Soini, Juha Tuukkanen, Sampsa Pikkarainen, Zoltán Lakó-Futó, Beatrix Sármán, L. Papp, Rudolf DeChâtel, Miklós Tóth, Heikki Ruskoaho, I. Szokodi

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

OBJECTIVE: The transcription factor nuclear factor-kappaB (NF-κB) has been implicated in cardiomyocyte hypertrophy in vitro as well as in vivo; however, it is unknown if activation of NF-κB plays a mandatory role in the hypertrophic process. Here we characterize the importance of NF-κB signaling in moderate and severe left ventricular (LV) hypertrophy in rats with chronic pressure overload induced by angiotensin II (Ang II) infusion. METHODS AND RESULTS: Electrophoretic mobility shift assay analysis revealed that Ang II infusion (2.5 μg/kg per min) for 6 days increased LV NF-κB/DNA-binding activity in a biphasic manner in Sprague-Dawley rats. Pyrrolidine dithiocarbamate (PDTC) (100 mg/kg per day), an NF-κB inhibitor, abolished Ang II-induced NF-κB activation and concomitant increase in tumor necrosis factor-α gene expression, while activator protein-1/DNA binding was not affected. Inhibition of NF-κB signaling for 6 days significantly attenuated Ang II-induced increases in LV/body weight ratio, LV mean wall thickness and cardiomyocyte cross-sectional area, without compromising LV systolic function. Moreover, PDTC abolished Ang II-induced cardiomyocyte apoptosis and interstitial fibrosis, and attenuated the gene expression of type I collagen. In contrast, a moderate LV hypertrophy induced by Ang II at a lower dose (0.5 μg/kg per min) was not associated with a significant activation of NF-κB, and PDTC treatment had no effect on the hypertrophic indices. CONCLUSION: Our in-vivo data indicate a critical role of NF-κB signaling in the advanced stage of the remodeling process, whereas development of moderate LV hypertrophy is not dependent on NF-κB activation.

Original languageEnglish
Pages (from-to)1927-1939
Number of pages13
JournalJournal of Hypertension
Volume25
Issue number9
DOIs
Publication statusPublished - Sep 2007

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Ventricular Remodeling
Angiotensin II
Left Ventricular Hypertrophy
Cardiac Myocytes
Gene Expression
DNA
Transcription Factor AP-1
Electrophoretic Mobility Shift Assay
Collagen Type I
Left Ventricular Function
Hypertrophy
Sprague Dawley Rats
Fibrosis
Transcription Factors
Tumor Necrosis Factor-alpha
Body Weight
Apoptosis
Pressure
pyrrolidine dithiocarbamic acid

Keywords

  • Angiotensin II
  • Apoptosis
  • Fibrosis
  • Hypertrophy
  • Nuclear factor-κB

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology

Cite this

Nuclear factor-κB signaling contributes to severe, but not moderate, angiotensin II-induced left ventricular remodeling. / Sármán, Balázs; Skoumal, R.; Leskinen, Hanna; Rysä, Jaana; Ilves, Mika; Soini, Ylermi; Tuukkanen, Juha; Pikkarainen, Sampsa; Lakó-Futó, Zoltán; Sármán, Beatrix; Papp, L.; DeChâtel, Rudolf; Tóth, Miklós; Ruskoaho, Heikki; Szokodi, I.

In: Journal of Hypertension, Vol. 25, No. 9, 09.2007, p. 1927-1939.

Research output: Contribution to journalArticle

Sármán, B, Skoumal, R, Leskinen, H, Rysä, J, Ilves, M, Soini, Y, Tuukkanen, J, Pikkarainen, S, Lakó-Futó, Z, Sármán, B, Papp, L, DeChâtel, R, Tóth, M, Ruskoaho, H & Szokodi, I 2007, 'Nuclear factor-κB signaling contributes to severe, but not moderate, angiotensin II-induced left ventricular remodeling', Journal of Hypertension, vol. 25, no. 9, pp. 1927-1939. https://doi.org/10.1097/HJH.0b013e3281e66653
Sármán, Balázs ; Skoumal, R. ; Leskinen, Hanna ; Rysä, Jaana ; Ilves, Mika ; Soini, Ylermi ; Tuukkanen, Juha ; Pikkarainen, Sampsa ; Lakó-Futó, Zoltán ; Sármán, Beatrix ; Papp, L. ; DeChâtel, Rudolf ; Tóth, Miklós ; Ruskoaho, Heikki ; Szokodi, I. / Nuclear factor-κB signaling contributes to severe, but not moderate, angiotensin II-induced left ventricular remodeling. In: Journal of Hypertension. 2007 ; Vol. 25, No. 9. pp. 1927-1939.
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abstract = "OBJECTIVE: The transcription factor nuclear factor-kappaB (NF-κB) has been implicated in cardiomyocyte hypertrophy in vitro as well as in vivo; however, it is unknown if activation of NF-κB plays a mandatory role in the hypertrophic process. Here we characterize the importance of NF-κB signaling in moderate and severe left ventricular (LV) hypertrophy in rats with chronic pressure overload induced by angiotensin II (Ang II) infusion. METHODS AND RESULTS: Electrophoretic mobility shift assay analysis revealed that Ang II infusion (2.5 μg/kg per min) for 6 days increased LV NF-κB/DNA-binding activity in a biphasic manner in Sprague-Dawley rats. Pyrrolidine dithiocarbamate (PDTC) (100 mg/kg per day), an NF-κB inhibitor, abolished Ang II-induced NF-κB activation and concomitant increase in tumor necrosis factor-α gene expression, while activator protein-1/DNA binding was not affected. Inhibition of NF-κB signaling for 6 days significantly attenuated Ang II-induced increases in LV/body weight ratio, LV mean wall thickness and cardiomyocyte cross-sectional area, without compromising LV systolic function. Moreover, PDTC abolished Ang II-induced cardiomyocyte apoptosis and interstitial fibrosis, and attenuated the gene expression of type I collagen. In contrast, a moderate LV hypertrophy induced by Ang II at a lower dose (0.5 μg/kg per min) was not associated with a significant activation of NF-κB, and PDTC treatment had no effect on the hypertrophic indices. CONCLUSION: Our in-vivo data indicate a critical role of NF-κB signaling in the advanced stage of the remodeling process, whereas development of moderate LV hypertrophy is not dependent on NF-κB activation.",
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AU - Sármán, Balázs

AU - Skoumal, R.

AU - Leskinen, Hanna

AU - Rysä, Jaana

AU - Ilves, Mika

AU - Soini, Ylermi

AU - Tuukkanen, Juha

AU - Pikkarainen, Sampsa

AU - Lakó-Futó, Zoltán

AU - Sármán, Beatrix

AU - Papp, L.

AU - DeChâtel, Rudolf

AU - Tóth, Miklós

AU - Ruskoaho, Heikki

AU - Szokodi, I.

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N2 - OBJECTIVE: The transcription factor nuclear factor-kappaB (NF-κB) has been implicated in cardiomyocyte hypertrophy in vitro as well as in vivo; however, it is unknown if activation of NF-κB plays a mandatory role in the hypertrophic process. Here we characterize the importance of NF-κB signaling in moderate and severe left ventricular (LV) hypertrophy in rats with chronic pressure overload induced by angiotensin II (Ang II) infusion. METHODS AND RESULTS: Electrophoretic mobility shift assay analysis revealed that Ang II infusion (2.5 μg/kg per min) for 6 days increased LV NF-κB/DNA-binding activity in a biphasic manner in Sprague-Dawley rats. Pyrrolidine dithiocarbamate (PDTC) (100 mg/kg per day), an NF-κB inhibitor, abolished Ang II-induced NF-κB activation and concomitant increase in tumor necrosis factor-α gene expression, while activator protein-1/DNA binding was not affected. Inhibition of NF-κB signaling for 6 days significantly attenuated Ang II-induced increases in LV/body weight ratio, LV mean wall thickness and cardiomyocyte cross-sectional area, without compromising LV systolic function. Moreover, PDTC abolished Ang II-induced cardiomyocyte apoptosis and interstitial fibrosis, and attenuated the gene expression of type I collagen. In contrast, a moderate LV hypertrophy induced by Ang II at a lower dose (0.5 μg/kg per min) was not associated with a significant activation of NF-κB, and PDTC treatment had no effect on the hypertrophic indices. CONCLUSION: Our in-vivo data indicate a critical role of NF-κB signaling in the advanced stage of the remodeling process, whereas development of moderate LV hypertrophy is not dependent on NF-κB activation.

AB - OBJECTIVE: The transcription factor nuclear factor-kappaB (NF-κB) has been implicated in cardiomyocyte hypertrophy in vitro as well as in vivo; however, it is unknown if activation of NF-κB plays a mandatory role in the hypertrophic process. Here we characterize the importance of NF-κB signaling in moderate and severe left ventricular (LV) hypertrophy in rats with chronic pressure overload induced by angiotensin II (Ang II) infusion. METHODS AND RESULTS: Electrophoretic mobility shift assay analysis revealed that Ang II infusion (2.5 μg/kg per min) for 6 days increased LV NF-κB/DNA-binding activity in a biphasic manner in Sprague-Dawley rats. Pyrrolidine dithiocarbamate (PDTC) (100 mg/kg per day), an NF-κB inhibitor, abolished Ang II-induced NF-κB activation and concomitant increase in tumor necrosis factor-α gene expression, while activator protein-1/DNA binding was not affected. Inhibition of NF-κB signaling for 6 days significantly attenuated Ang II-induced increases in LV/body weight ratio, LV mean wall thickness and cardiomyocyte cross-sectional area, without compromising LV systolic function. Moreover, PDTC abolished Ang II-induced cardiomyocyte apoptosis and interstitial fibrosis, and attenuated the gene expression of type I collagen. In contrast, a moderate LV hypertrophy induced by Ang II at a lower dose (0.5 μg/kg per min) was not associated with a significant activation of NF-κB, and PDTC treatment had no effect on the hypertrophic indices. CONCLUSION: Our in-vivo data indicate a critical role of NF-κB signaling in the advanced stage of the remodeling process, whereas development of moderate LV hypertrophy is not dependent on NF-κB activation.

KW - Angiotensin II

KW - Apoptosis

KW - Fibrosis

KW - Hypertrophy

KW - Nuclear factor-κB

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