Abstract 1711: Increased Incidence of Infarct Rupture in Mice With a Mutant Form of alphaE Catenin
Background Infarct rupture is a usually fatal complication of myocardial infarction (MI) in humans, which typically occurs at 3–7 days after MI. The molecular mechanisms that lead to infarct rupture in humans are poorly understood. Animal studies have demonstrated an increased invasion of inflammatory cells and increased matrix metalloproteinase (MMP) activity in ruptured infarcts. In a previous study, we have confirmed the increased MMP activity in samples from ruptured human infarcts. We also observed the lack of localization of alphaE-catenin, a component of the cell adhesion complex, to the intercalated disks of the cardiomyocytes in hearts with a ruptured infarct. This suggests a diminished cell adhesion in these hearts, which could lead to accelerated invasion of inflammatory cells, increased production and acitvation of MMPs in the infarct area and eventually infarct rupture.
Methods To investigate the role of alphaE-catenin in the development of infarct rupture, we induced MI through permanent occlusion of the LAD coronary artery in mice heterozygous for a C-terminal truncation (AA 632–906) of alphaE-catenin in a 129S1 background. The lack of the C-terminal part of alphaE-catenin prevents its association with intracellular F-actin fibers, thereby destabilizing the cell adhesion complex. Homozygous mutants are not viable and could therefore not be used for this study.
Results Infarct rupture occurred in 10/18 heterozygous mice and in 3/18 wildtype littermates (P=0.013). Western blotting with an antibody directed against the C-terminus of alphaE-catenin showed a 2.1-fold lower amount of this protein in the uninjured septa of in the infarct rupture group (P<0.001).
Conclusion These data show a causal relationship between alphaE-catenin levels in cardiomyocytes and infarct rupture. Therefore we conclude that a defective cell adhesion complex can predispose to infarct rupture after myocardial infarction.