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. 2011;6(11):e27923.
doi: 10.1371/journal.pone.0027923. Epub 2011 Nov 28.

Alterations in the interleukin-1/interleukin-1 receptor antagonist balance modulate cardiac remodeling following myocardial infarction in the mouse

Antonio Abbate  1 , Fadi N Salloum, Benjamin W Van Tassell, Elena Vecile, Stefano Toldo, Ignacio Seropian, Eleonora Mezzaroma, Aldo Dobrina
Affiliations

Alterations in the interleukin-1/interleukin-1 receptor antagonist balance modulate cardiac remodeling following myocardial infarction in the mouse

Antonio Abbate et al. PLoS One. 2011.

Abstract

Background: Healing after acute myocardial infarction (AMI) is characterized by an intense inflammatory response and increased Interleukin-1 (IL-1) tissue activity. Genetically engineered mice lacking the IL-1 receptor (IL-1R1-/-, not responsive to IL-1) or the IL-1 receptor antagonist (IL-1Ra, enhanced response to IL-1) have an altered IL-1/IL-1Ra balance that we hypothesize modulates infarct healing and cardiac remodeling after AMI.

Methods: IL-1R1-/- and IL-1Ra-/- male mice and their correspondent wild-types (WT) were subjected to permanent coronary artery ligation or sham surgery. Infarct size (trichrome scar size), apoptotic cell death (TUNEL) and left ventricular (LV) dimensions and function (echocardiography) were measured prior to and 7 days after surgery.

Results: When compared with the corresponding WT, IL-1R1-/- mice had significantly smaller infarcts (-25%), less cardiomyocyte apoptosis (-50%), and reduced LV enlargement (LV end-diastolic diameter increase [LVEDD], -20%) and dysfunction (LV ejection fraction [LVEF] decrease, -50%), whereas IL-1Ra-/- mice had significantly larger infarcts (+75%), more apoptosis (5-fold increase), and more severe LV enlargement (LVEDD increase,+30%) and dysfunction (LVEF decrease, +70%)(all P values <0.05).

Conclusions: An imbalance in IL-1/IL-1Ra signaling at the IL-1R1 level modulates the severity of cardiac remodeling after AMI in the mouse, with reduced IL-1R1 signaling providing protection and unopposed IL-1R1 signaling providing harm.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Body weight and left ventricular mass in IL-1R1-/- and IL-1Ra-/- mice.
Genetically modified mice (both IL-1R1-/- and IL-1Ra-/- ) have significantly smaller body weights compared with the respective wild-type animals (WT). Left ventricular (LV) mass calculated at echocardiography was not statistically different comparing IL-1R1-/- and IL-1Ra-/- and respectively WT, but the IL-1R1-/- had significantly greater LV mass/weight ratio. N = 8–10 per group.
Figure 2
Figure 2. Infarct size, apoptosis and left ventricular remodeling in wild-type and IL-1R1-/- mice.
When compared with the corresponding wild-type mice, infarct scar size (Masson's trichrome stain) and cardiomyocyte apoptotic rate (in-situ end labelling of DNA fragmentation–TUNEL) were significantly smaller in IL-1R1-/- mice. Moreover, IL-1R1-/- mice had less left ventricular enlargement and systolic dysfunction 1 week after AMI. N = 6–8 per group.
Figure 3
Figure 3. Infarct size, apoptosis and left ventricular remodeling in wild-type and IL-1Ra-/- mice.
When compared with the corresponding wild-type mice, infarct scar size (Masson's trichrome stain) and cardiomyocyte apoptotic rate (in-situ end labelling of DNA fragmentation–TUNEL) were significantly greater in IL-1Ra-/- mice. Moreover, IL-1Ra-/- mice had less left ventricular enlargement and systolic dysfunction 1 week after AMI. N = 6–8 per group.
Figure 4
Figure 4. Indirect comparison between the IL-1R1-/- and the IL-1Ra-/-.
Considering that IL-1R1-/- and the IL-1Ra-/- mice were generated in different backgrounds, a direct comparison between the 2 strains cannot be made. The Figure shows an indirect comparison between the 2 strains in which the value of each strain is normalized to the corresponding wild-type mouse. In the comparison, the IL-1R1-/- mouse shows to have smaller infarcts, less apoptosis and more favorable remodeling, wheras the IL-1Ra-/- mouse shows large infarcts, more apoptosis, and more unfavorable remodeling.
See this image and copyright information in PMC

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