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.
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.


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.


CONCLUSIONS
Taken together, our results suggest IL-10 treatment as a potential therapeutic approach to limit the progression of pressure overload-induced adverse cardiac remodeling.
Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, 303 E Superior St, Chicago IL 60611, USA.
Suresh Kumar
SK
Verma
Prasanna
P
Krishnamurthy
David
D
Barefield
Neha
N
Singh
Rajesh
R
Gupta
Erin
E
Lambers
Melissa
M
Thal
Alexander
A
Mackie
Eneda
E
Hoxha
Veronica
V
Ramirez
Gangjian
G
Qin
Sakthivel
S
Sadayappan
Asish K
AK
Ghosh
Raj
R
Kishore
D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005355:Fibrosis; D016753:Interleukin-10 / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use*; D007545:Isoproterenol / Q000009:adverse effects / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10; D007545:Isoproterenol