Interleukin-10 treatment attenuates pressure overload-induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3-dependent inhibition of nuclear factor-κB

Suresh Kumar Verma, Prasanna Krishnamurthy, David Barefield, Neha Singh, Rajesh Gupta, Erin Lambers, Melissa Thal, Alexander MacKie, Eneda Hoxha, Veronica Ramirez, Gangjian Qin, Sakthivel Sadayappan, Asish K. Ghosh, Raj Kishore*

*Corresponding author for this work

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Background-: Inflammation plays a critical role in adverse cardiac remodeling and heart failure. Therefore, approaches geared toward inhibiting inflammation may provide therapeutic benefits. We tested the hypotheses that genetic deletion of interleukin-10 (IL-10), a potent antiinflammatory cytokine, exacerbates pressure overload-induced adverse cardiac remodeling and hypertrophy and that IL-10 therapy inhibits this pathology. Methods and Results-: Cardiac hypertrophy was induced in wild-type and IL-10 knockout mice by isoproterenol (ISO) infusion. ISO-induced left ventricular dysfunction and hypertrophic remodeling, including fibrosis and fetal gene expression, were further exaggerated in knockout mice compared with wild-type mice. Systemic recombinant mouse IL-10 administration markedly improved left ventricular function and not only inhibited but also reversed ISO-induced cardiac remodeling. Intriguingly, a very similar cardioprotective response of IL-10 was found in transverse aortic constriction-induced hypertrophy and heart failure models. In neonatal rat ventricular myocytes and H9c2 myoblasts, ISO activated nuclear factor-κB and inhibited signal transducers and activators of transcription 3 (STAT3) phosphorylation. Interestingly, IL-10 suppressed ISO-induced nuclear factor-κB activation and attenuated STAT3 inhibition. Moreover, pharmacological and genetic inhibition of STAT3 reversed the protective effects of IL-10, whereas ectopic expression of constitutively active STAT3 mimicked the IL-10 responses on the ISO effects, confirming that the IL-10-mediated inhibition of nuclear factor-κB is STAT3 dependent. Conclusion-: Taken together, our results suggest IL-10 treatment as a potential therapeutic approach to limit the progression of pressure overload-induced adverse cardiac remodeling.

Original languageEnglish (US)
Pages (from-to)418-429
Number of pages12
JournalCirculation
Volume126
Issue number4
DOIs
StatePublished - Jul 24 2012

Fingerprint

STAT3 Transcription Factor
Interleukin-10
Pressure
Isoproterenol
Heart Failure
Cardiomegaly
Knockout Mice
Inflammation
Myoblasts
Left Ventricular Dysfunction
Left Ventricular Function
Constriction
Muscle Cells
Hypertrophy
Fibrosis
Anti-Inflammatory Agents
Therapeutics
Phosphorylation
Pharmacology
Pathology

Keywords

  • apoptosis
  • heart failure
  • hypertrophy
  • interleukins
  • myocardium
  • remodeling
  • signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Verma, Suresh Kumar ; Krishnamurthy, Prasanna ; Barefield, David ; Singh, Neha ; Gupta, Rajesh ; Lambers, Erin ; Thal, Melissa ; MacKie, Alexander ; Hoxha, Eneda ; Ramirez, Veronica ; Qin, Gangjian ; Sadayappan, Sakthivel ; Ghosh, Asish K. ; Kishore, Raj. / Interleukin-10 treatment attenuates pressure overload-induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3-dependent inhibition of nuclear factor-κB. In: Circulation. 2012 ; Vol. 126, No. 4. pp. 418-429.
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abstract = "Background-: Inflammation plays a critical role in adverse cardiac remodeling and heart failure. Therefore, approaches geared toward inhibiting inflammation may provide therapeutic benefits. We tested the hypotheses that genetic deletion of interleukin-10 (IL-10), a potent antiinflammatory cytokine, exacerbates pressure overload-induced adverse cardiac remodeling and hypertrophy and that IL-10 therapy inhibits this pathology. Methods and Results-: Cardiac hypertrophy was induced in wild-type and IL-10 knockout mice by isoproterenol (ISO) infusion. ISO-induced left ventricular dysfunction and hypertrophic remodeling, including fibrosis and fetal gene expression, were further exaggerated in knockout mice compared with wild-type mice. Systemic recombinant mouse IL-10 administration markedly improved left ventricular function and not only inhibited but also reversed ISO-induced cardiac remodeling. Intriguingly, a very similar cardioprotective response of IL-10 was found in transverse aortic constriction-induced hypertrophy and heart failure models. In neonatal rat ventricular myocytes and H9c2 myoblasts, ISO activated nuclear factor-κB and inhibited signal transducers and activators of transcription 3 (STAT3) phosphorylation. Interestingly, IL-10 suppressed ISO-induced nuclear factor-κB activation and attenuated STAT3 inhibition. Moreover, pharmacological and genetic inhibition of STAT3 reversed the protective effects of IL-10, whereas ectopic expression of constitutively active STAT3 mimicked the IL-10 responses on the ISO effects, confirming that the IL-10-mediated inhibition of nuclear factor-κB is STAT3 dependent. Conclusion-: Taken together, our results suggest IL-10 treatment as a potential therapeutic approach to limit the progression of pressure overload-induced adverse cardiac remodeling.",
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author = "Verma, {Suresh Kumar} and Prasanna Krishnamurthy and David Barefield and Neha Singh and Rajesh Gupta and Erin Lambers and Melissa Thal and Alexander MacKie and Eneda Hoxha and Veronica Ramirez and Gangjian Qin and Sakthivel Sadayappan and Ghosh, {Asish K.} and Raj Kishore",
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Verma, SK, Krishnamurthy, P, Barefield, D, Singh, N, Gupta, R, Lambers, E, Thal, M, MacKie, A, Hoxha, E, Ramirez, V, Qin, G, Sadayappan, S, Ghosh, AK & Kishore, R 2012, 'Interleukin-10 treatment attenuates pressure overload-induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3-dependent inhibition of nuclear factor-κB', Circulation, vol. 126, no. 4, pp. 418-429. https://doi.org/10.1161/CIRCULATIONAHA.112.112185

Interleukin-10 treatment attenuates pressure overload-induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3-dependent inhibition of nuclear factor-κB. / Verma, Suresh Kumar; Krishnamurthy, Prasanna; Barefield, David; Singh, Neha; Gupta, Rajesh; Lambers, Erin; Thal, Melissa; MacKie, Alexander; Hoxha, Eneda; Ramirez, Veronica; Qin, Gangjian; Sadayappan, Sakthivel; Ghosh, Asish K.; Kishore, Raj.

In: Circulation, Vol. 126, No. 4, 24.07.2012, p. 418-429.

Research output: Contribution to journalArticle

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T1 - Interleukin-10 treatment attenuates pressure overload-induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3-dependent inhibition of nuclear factor-κB

AU - Verma, Suresh Kumar

AU - Krishnamurthy, Prasanna

AU - Barefield, David

AU - Singh, Neha

AU - Gupta, Rajesh

AU - Lambers, Erin

AU - Thal, Melissa

AU - MacKie, Alexander

AU - Hoxha, Eneda

AU - Ramirez, Veronica

AU - Qin, Gangjian

AU - Sadayappan, Sakthivel

AU - Ghosh, Asish K.

AU - Kishore, Raj

PY - 2012/7/24

Y1 - 2012/7/24

N2 - Background-: Inflammation plays a critical role in adverse cardiac remodeling and heart failure. Therefore, approaches geared toward inhibiting inflammation may provide therapeutic benefits. We tested the hypotheses that genetic deletion of interleukin-10 (IL-10), a potent antiinflammatory cytokine, exacerbates pressure overload-induced adverse cardiac remodeling and hypertrophy and that IL-10 therapy inhibits this pathology. Methods and Results-: Cardiac hypertrophy was induced in wild-type and IL-10 knockout mice by isoproterenol (ISO) infusion. ISO-induced left ventricular dysfunction and hypertrophic remodeling, including fibrosis and fetal gene expression, were further exaggerated in knockout mice compared with wild-type mice. Systemic recombinant mouse IL-10 administration markedly improved left ventricular function and not only inhibited but also reversed ISO-induced cardiac remodeling. Intriguingly, a very similar cardioprotective response of IL-10 was found in transverse aortic constriction-induced hypertrophy and heart failure models. In neonatal rat ventricular myocytes and H9c2 myoblasts, ISO activated nuclear factor-κB and inhibited signal transducers and activators of transcription 3 (STAT3) phosphorylation. Interestingly, IL-10 suppressed ISO-induced nuclear factor-κB activation and attenuated STAT3 inhibition. Moreover, pharmacological and genetic inhibition of STAT3 reversed the protective effects of IL-10, whereas ectopic expression of constitutively active STAT3 mimicked the IL-10 responses on the ISO effects, confirming that the IL-10-mediated inhibition of nuclear factor-κB is STAT3 dependent. Conclusion-: Taken together, our results suggest IL-10 treatment as a potential therapeutic approach to limit the progression of pressure overload-induced adverse cardiac remodeling.

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KW - heart failure

KW - hypertrophy

KW - interleukins

KW - myocardium

KW - remodeling

KW - signal transduction

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