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.
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.
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DOI：
10.1161/circulationaha.112.112185
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发表时间：
2012-07-24
期刊：
影响因子：
37.8
通讯作者：
Kishore R
中科院分区：
文献类型：
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作者：
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
炎症在不良心脏重塑和心力衰竭中起关键作用。因此，针对抑制炎症的方法可以提供治疗益处。我们检验了这样的假设，即白细胞介素-10（IL-10）（一种有效的抗炎细胞因子）的基因缺失加剧了压力超负荷诱导的不良心脏重塑和肥大，而IL-10治疗抑制了这种病理。通过输注异丙肾上腺素（ISO）在野生型（WT）和IL 10敲除（KO）小鼠中诱导心脏肥大。与WT相比，KO小鼠中ISO诱导的左心室（LV）功能障碍和肥厚性重塑（包括纤维化和胎儿基因表达）进一步加重。全身性重组小鼠IL 10给药显著改善LV功能，不仅抑制而且逆转ISO诱导的心脏重塑。有趣的是，在横主动脉缩窄（TAC）诱导的肥大和心力衰竭模型中发现了非常相似的心脏保护作用。在新生大鼠心室肌细胞（NRCM）和H9 c2成肌细胞中，ISO激活NFκB B，同时抑制STAT 3磷酸化。有趣的是，IL 10抑制了ISO诱导的NFκB活化，减弱了STAT 3抑制。此外，STAT 3的药理学和遗传学抑制逆转了IL 10的保护作用，而组成性活性STAT 3的异位表达模拟了IL 10对ISO效应的反应，证实了IL 10介导的NFκB抑制是STAT 3依赖性的。总之，我们的研究表明，IL 10治疗作为一种潜在的治疗方法，以限制压力超负荷诱导的不良心脏重塑的进展。
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. 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. Taken together our studies suggest IL10 treatment as a potential therapeutic approach to limit the progression of pressure overload-induced adverse cardiac remodeling.