Abstract P138: PTEN Mediates Post--Myocardial Infarction Remodeling
Background- Following myocardial infarction (MI), innate immunity is activated, leading to cytokine production and initiation of inflammation. Interleukin (IL)-10 has been reported to attenuate post-MI remodeling by inhibiting expression of tumor necrosis factor (TNF)-α. The phosphatase and tensin homologue deleted on chromosome ten (PTEN) plays an important role in myocardial ischemia-reperfusion injury. It is not known whether PTEN regulates cytokine production and cardiac remodeling. Here, we have investigated the hypothesis that PTEN mediates post-MI remodeling by inhibiting IL-10.
Methods and Results- MI was induced in wildtype (WT) mice and Pten heterozygous (HET) mice. In a separate experiment, Pten adenoviruses or empty viruses were injected into the peri-infarct area of WT mice. Left ventricular (LV) anatomical and functional changes were assessed by echocardiography. Mononuclear cell infiltration was measured by histology. TNF-α, IL-10, matrix metalloproteinase (MMP)-2 and MMP-9 protein levels were analyzed in the peri-infarct area. At the end of the experiments, LV end-diastolic diameter (LVEDD) was decreased and fractional shortening (FS) was increased in HET mice compared with WT mice (LVEDD: 4.13±0.22 vs. 5.42±0.26 mm, p<0.01; FS: 21.9±2.6 vs. 11.5±1.1 %, p<0.001). Moreover, heart weight and infarct size were decreased in HET mice compared with WT mice. However, FS was decreased and LV rupture (LVR) was increased in Pten adenovirus-treated mice compared with empty vector-treated mice [FS: 8.2±1.1 vs. 21.5±3.2 %, p < 0.01; LVR: 100% (16/16) vs. 33% (3/9)]. Mononuclear cell infiltration was attenuated in HET mice and worsened in Pten adenovirus-treated mice. IL-10 protein levels were upregulated and TNF-α, MMP-2, and MMP-9 protein levels were downregulated in HET mice. The opposite effects were found in Pten over-expressing hearts.
Conclusions- PTEN downregulation increases IL-10 production and inhibits inflammatory responses and attenuates cardiac remodeling; conversely, PTEN over-expression inhibits IL-10 expression and increases cardiac injury. Therefore, our studies demonstrate that PTEN mediates post-MI remodeling, at least in part, by regulating IL-10 production.
- © 2011 by American Heart Association, Inc.