TY - JOUR
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.
AB - 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.
KW - apoptosis
KW - heart failure
KW - hypertrophy
KW - interleukins
KW - myocardium
KW - remodeling
KW - signal transduction
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U2 - 10.1161/CIRCULATIONAHA.112.112185
DO - 10.1161/CIRCULATIONAHA.112.112185
M3 - Article
C2 - 22705886
AN - SCOPUS:84864277489
SN - 0009-7322
VL - 126
SP - 418
EP - 429
JO - Circulation
JF - Circulation
IS - 4
ER -