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A Murine Closed-chest Model of Myocardial Ischemia and Reperfusion
Published on: July 17, 2012
Cardiac gene expression and systemic cytokine profile are complementary in a murine model of post-ischemic heart
S Lachtermacher1, B L B Esporcatte, F Montalvão
1Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
Insights
Myocardial infarction (MI) triggers immune responses, leading to heart failure (HF). This study reveals increased antibodies and inflammatory cytokines in mice post-MI, alongside significant cardiac gene changes, highlighting immune system involvement in heart remodeling.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Biology
Background:
- Myocardial infarction (MI) can precipitate heart failure (HF) through immune system activation and ventricular remodeling.
- The interplay between systemic changes and cardiac alterations in chronic ischemia remains incompletely understood.
Purpose of the Study:
- To investigate cardiac gene expression and systemic cytokine profiles in a mouse model of post-ischemic heart failure.
- To explore immune-mediated mechanisms contributing to cardiac remodeling after MI.
Main Methods:
- Analysis of plasma for IgM, IgG anti-heart antibodies, and inflammatory cytokines.
- Gene expression profiling of heart tissue using microarrays.
- Quantification of specific inflammatory response genes.
Main Results:
- Significant increases in total serum IgM (5.2-fold) and IgG (3.6-fold) with anti-heart specificity were observed.
- Elevated levels of pro-inflammatory cytokines (IL-1beta, TNF-alpha, IFN-gamma) and chemokines (MCP-1, IL-8) in infarcted mice.
- Over 2000 cardiac genes were significantly regulated, with complement activation and immune response pathways being notably upregulated.
Conclusions:
- Post-ischemic heart failure is associated with robust systemic immune activation, including increased autoantibodies and inflammatory mediators.
- Cardiac remodeling in this model involves significant alterations in gene expression, particularly within immune and inflammatory pathways.
- Immune-mediated mechanisms play a critical role both systemically and locally in the progression of heart failure after myocardial infarction.
Abstract:
After myocardial infarction (MI), activation of the immune system and inflammatory mechanisms, among others, can lead to ventricular remodeling and heart failure (HF). The interaction between these systemic alterations and corresponding changes in the heart has not been extensively examined in the setting of chronic ischemia. The main purpose of this study was to investigate alterations in cardiac gene and systemic cytokine profile in mice with post-ischemic HF. Plasma was tested for IgM and IgG anti-heart reactive repertoire and inflammatory cytokines. Heart samples were assayed for gene expression by analyzing hybridization to AECOM 32k mouse microarrays. Ischemic HF significantly increased the levels of total serum IgM (by 5.2-fold) and total IgG (by 3.6-fold) associated with a relatively high content of anti-heart specificity. A comparable increase was observed in the levels of circulating pro-inflammatory cytokines such as IL-1beta (3.8X) and TNF-alpha (6.0X). IFN-gamma was also increased by 3.1-fold in the MI group. However, IL-4 and IL-10 were not significantly different between the MI and sham-operated groups. Chemokines such as MCP-1 and IL-8 were 1.4- and 13-fold increased, respectively, in the plasma of infarcted mice. We identified 2079 well annotated unigenes that were significantly regulated by post-ischemic HF. Complement activation and immune response were among the most up-regulated processes. Interestingly, 21 of the 101 quantified unigenes involved in the inflammatory response were significantly up-regulated and none were down-regulated. These data indicate that post-ischemic heart remodeling is accompanied by immune-mediated mechanisms that act both systemically and locally.
