UltraRapid Communication IL10 Inhibits Inflammation and Attenuates Left Ventricular Remodeling After Myocardial Infarction via Activation of STAT3 and Suppression of HuR (original) (raw)
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Circulation Research, 2009
Persistent inflammatory response has adverse effects on left ventricular (LV) function and remodeling following acute myocardial infarction (AMI). We hypothesized that suppression of inflammation with IL-10 treatment attenuates LV dysfunction and remodeling after AMI. After the induction of AMI, mice were treated with either saline or recombinant IL-10, and inflammatory response and LV functional and structural remodeling changes were evaluated. IL-10 significantly suppressed infiltration of inflammatory cells and expression of inflammatory cytokines in the myocardium. These changes were associated with IL-10-mediated inhibition of p38 MAP kinase activation and repression of cytokine mRNA stabilizing protein, HuR. IL-10 treatment significantly improved LV functions, reduced infarct size and attenuated infarct wall thinning. MI-induced increase in MMP9 expression and activity was associated with increased fibrosis since IL-10 treatment reduced both MMP9 activity and fibrosis. siRNA knockdown of HuR mimicked IL-10 mediated reduction in MMP-9 expression and activity in NIH3T3 cells. Moreover, IL-10 treatment significantly increased capillary density in the infarcted myocardium which was associated with enhanced STAT3 phosphorylation. Taken together, our studies demonstrate that IL-10 suppresses inflammatory response and contributes to improved LV function and remodeling by inhibiting fibrosis via suppression of HuR/MMP9 and by enhancing capillary density through activation of STAT3.
IL-10 inhibits inflammation and attenuates left ventricular remodeling after MI.
Persistent inflammatory response has adverse effects on left ventricular (LV) function and remodeling following acute myocardial infarction (AMI). We hypothesized that suppression of inflammation with IL-10 treatment attenuates LV dysfunction and remodeling after AMI. After the induction of AMI, mice were treated with either saline or recombinant IL-10, and inflammatory response and LV functional and structural remodeling changes were evaluated. IL-10 significantly suppressed infiltration of inflammatory cells and expression of inflammatory cytokines in the myocardium. These changes were associated with IL-10-mediated inhibition of p38 MAP kinase activation and repression of cytokine mRNA stabilizing protein, HuR. IL-10 treatment significantly improved LV functions, reduced infarct size and attenuated infarct wall thinning. MI-induced increase in MMP9 expression and activity was associated with increased fibrosis since IL-10 treatment reduced both MMP9 activity and fibrosis. siRNA knockdown of HuR mimicked IL-10 mediated reduction in MMP-9 expression and activity in NIH3T3 cells. Moreover, IL-10 treatment significantly increased capillary density in the infarcted myocardium which was associated with enhanced STAT3 phosphorylation. Taken together, our studies demonstrate that IL-10 suppresses inflammatory response and contributes to improved LV function and remodeling by inhibiting fibrosis via suppression of HuR/MMP9 and by enhancing capillary density through activation of STAT3.
Basic research in cardiology, 2017
Inflammation resolution is important for scar formation following myocardial infarction (MI) and requires the coordinated actions of macrophages and fibroblasts. In this study, we hypothesized that exogenous interleukin-10 (IL-10), an anti-inflammatory cytokine, promotes post-MI repair through actions on these cardiac cell types. To test this hypothesis, C57BL/6J mice (male, 3- to 6-month old, n = 24/group) were treated with saline or IL-10 (50 μg/kg/day) by osmotic mini-pump infusion starting at day (d) 1 post-MI and sacrificed at d7 post-MI. IL-10 infusion doubled plasma IL-10 concentrations by d7 post-MI. Despite similar infarct areas and mortality rates, IL-10 treatment significantly decreased LV dilation (1.6-fold for end-systolic volume and 1.4-fold for end-diastolic volume) and improved ejection fraction 1.8-fold (both p < 0.05). IL-10 treatment attenuated inflammation at d7 post-MI, evidenced by decreased numbers of Mac-3-positive macrophages in the infarct (p < 0.05)....
Arquivos Brasileiros de Cardiologia, 2010
Background: Recent studies show that the expression of inflammatory mediators, such as cytokines, is an important factor for the development and progression of heart failure (HF), especially in the presence of left ventricular dysfunction. These changes have been demonstrated both in the plasma and heart muscle and, more recently, in skeletal muscle of rats and in patients with HF. Objective: To investigate the production and expression of tumor necrosis factor-α (TNF) and interleukin-10 (IL-10) in the soleus and the extensor digitorum longus (EDL) muscles of animals with left ventricular dysfunction after myocardial infarction (MI). Methods: We used male Wistar rats that underwent ligation of the left coronary artery without reperfusion. Four weeks after this procedure, the animals underwent echocardiography and were divided into the following experimental groups: sham operated (sham) and IM. They remained under observation for a further period of 8 weeks. Results: The level of the cytokine TNF-α increased by 26.5% (p <0.05), and its gene expression increased 3 times (p <0.01). The level of IL-10 decreased by 38.2% (p <0.05). Both changes occurred only in the soleus muscle, with no change in the EDL. The decrease (36.5%, p <0.05) in the IL-10/TNF-α ratio was due to both increased tissue levels of TNF-α and decreased tissue levels of IL-10. Conclusion: Our results showed significant changes in the IL-10/TNF-α ratio, which may have an additive role in the assessment of deterioration and progression of left ventricular dysfunction post-MI. Furthermore, our study suggests that these changes seem to be related to the muscle fiber type. (Arq Bras Cardiol 2010; 94(3):293-300
Prolonged inflammatory response is associated with left ventricular (LV) dysfunction and adverse remodeling following myocardial infarction (MI). IL-10 inhibits inflammation by suppressing HuR-mediated mRNA stabilization of proinflammatory cytokines. Here we report that following MI, IL-10 ؊/؊ mice showed exaggerated LV dysfunction, fibrosis, and cardiomyocyte apoptosis. Short-hairpin RNA (shRNA)-mediated knockdown of HuR in the myocardium significantly reversed MI-induced LV dysfunctions and LV remodeling. HuR knockdown significantly reduced MI-induced cardiomyocyte apoptosis concomitant with reduced p53 expression. Moreover, HuR knockdown significantly reduced infarct size and fibrosis area, which in turn was associated with decreased TGF- expression. In vitro, stable knockdown of HuR in mouse macrophage cell line RAW 264.7 corroborated in vivo data and revealed reduced mRNA expression of TNF-␣, TGF-, and p53 following LPS challenge, which was associated with a marked reduction in the mRNA stability of these genes. Taken together, our studies suggest that HuR is a direct target of IL-10, and HuR knockdown mimics anti-inflammatory effects of IL-10.-Krishnamurthy, P., Lambers, E., Verma, S., Thorne, T., Qin, G., Losordo, D. W., Kishore, R. Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI inflammatory response and left ventricular dysfunction in IL-10-null mice. FASEB J. 24, 2484 -2494 (2010). www.fasebj.org