Abstract 229: MRL Mice Prevent Incidence of Cardiac Rupture by a Unique Collagen Synthesis and Degradation after Myocardial Infarction
Background: MRL mice have the unique capacity of repairing skin or ear hole wound without scar formation. To determine their fate following myocardial infarction (MI), and potential matrix modulation, we compared MRL mice (potentially good healers) with C57Bl/6 control mice (potentially poor healers).
Methods: Large MI was created by the standard left coronary artery ligation procedure in 10–12 weeks old MRL (n=22) and C57Bl/6 mice (n=34). Survival curve was evaluated by Kaplan-Meier proportional hazard model, and myocardial scar size was determined by Masson’s trichrome staining and digital quantification. Myocardial gelatinolytic activity in the infarcted and border zones was analyzed by substrate zymography. Pro-collagen type I and type III, as well as tissue inhibitor of matrix metalloprotease-1 (TIMP-1) and 4 (TIMP-4) mRNA levels were determined by real-time PCR.
Results: At 35 days after infarction, the survival rate was significantly higher in the MRL mice compared to the C57Bl/6 (MRL mice, 77% vs. C57Bl/6 mice, 29%, p<0.05). The main cause of death within 7 days in C57Bl/6 mice was cardiac rupture (68%), which was not observed at all in the MRL mice (0%). At day 35 post-MI, both strains of mice had similar infarct size and scar formation. At day 3, activation ratios of pro-matrix metalloprotease (MMP)-2 in the infarcted and border zones were significantly greater in C57Bl/6 mice than MRL mice. In contrast, activation ratios of pro-MMP-9 were not different between the MRL and C57Bl/6 mice. On the other hand, TIMP-1 expression was also significantly increased in the rupture resistant MRL mice when compared to the susceptible C57Bl/6 mice (p<0.05), but no differences were found between the MRL and C57Bl/6 mice in terms of TIMP-4, pro-collagen type I and III expression.
Conclusion: MRL mice had a significant improvement in survival rate when compared to C57Bl/6 mice mainly due to a complete resistance to ventricular rupture. MRL mice had significantly lower pro-MMP-2 activation and higher TIMP-1 expression, suggesting a uniquely protective profile of matrix dynamics with potential therapeutic implications.