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 Article (Web of Science)

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.

authors

  • 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

publication date

  • 2012

webpage

published in

number of pages

  • 11

start page

  • 418

end page

  • 429

volume

  • 126

issue

  • 4