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

Abstract

Background Inflammation plays a critical role in adverse cardiac remodeling and heart failure. Therefore, approaches geared towards inhibiting inflammation may provide therapeutic benefits. We tested the hypothesis that genetic deletion of interleukin-10 (IL10), a potent anti-inflammatory cytokine, exacerbates pressure-overload induced adverse cardiac remodeling and hypertrophy and that IL10 therapy inhibits this pathology. Methods and Results Cardiac hypertrophy was induced in Wild-type (WT) and IL10-knockout (KO) mice by isoproterenol (ISO) infusion. ISO-induced left ventricular (LV) dysfunction and hypertrophic remodeling, including fibrosis and fetal gene expression, were further exaggerated in KO mice compared to WT. Systemic recombinant mouse IL10 administration markedly improved LV function and not only inhibited but also reversed ISO-induced cardiac remodeling. Intriguingly, very similar cardio-protective response of IL10 was found in transverse aortic constriction (TAC)-induced hypertrophy and heart failure model. In neonatal rat ventricular myocytes (NRCM) and H9c2 myoblasts, ISO activated NFκB while it inhibited STAT3 phosphorylation. Interestingly, IL10 suppressed ISO-induced NFκB activation and attenuated STAT3 inhibition. Moreover, pharmacological and genetic inhibition of STAT3 reversed the protective effects of IL10 while ectopic expression of constitutively active STAT3 mimicked the IL10 responses on the ISO effects, confirming that IL10 mediated inhibition of NFκB is STAT3 dependent. Conclusions Taken together our studies suggest IL10 treatment as a potential therapeutic approach to limit the progression of pressure overload-induced adverse cardiac remodeling.

Extracellular high‐mobility group box 1 mediates pressure overload‐induced cardiac hypertrophy and heart failure

“…Evidence suggest that inflammation is involved in the progression of pressure overload‐induced cardiac hypertrophy and heart failure, but the mechanisms have not yet been fully characterized 3, 4, 5. In the present study, we addressed the potential contribution of local HMGB1 in pressure overload‐induced cardiac hypertrophy and LV dysfunction.…”

“…Although it is widely accepted that inflammation including various cytokines and receptors are involved in the pathological process of pressure overload‐induced cardiac hypertrophy and cardiac dysfunction 3, 4, 5, the molecular mechanisms underlying the progression of cardiac hypertrophy and succedent heart failure have not yet been completely defined.…”

Regenerative Wound Healing: The Role of Interleukin-10

“…Myocardial infarction has many similarities to cutaneous wound healing, including an induced inflammatory response and the requirement of neo-vascularization to repair injured tissue. 40 In IL-10 -/ -mice, there is a deficiency in EPC recruitment. 6 Further, treatment with IL-10 results in increased EPC survival and angiogenesis, 6 as well as an attenuated inflammatory response, decreased fibrosis, and preservation of cardiac function.…”

Heart Failure With Anemia

“…Interestingly, IL-10 was recently proposed as a potential therapeutic approach to limit the progression of pressure overload-induced adverse cardiac remodeling. 23 However, volume overload seems to be a concern in patients with HF and anemia.…”