Abstract 13984: What’s the Best Age for Mice to Have Myocardial Infarction: Modulating Matrix Metalloproteinase-9 to Answer the Question
Previously, we reported that matrix metalloproteinase-9 (MMP-9) levels increase post-myocardial infarction (MI), and MMP-9 deletion in young mice attenuates remodeling of the left ventricle (LV) and improves cardiac function post-MI. We also showed that MMP-9 increases with age, accompanied by decreased end diastolic function. In this study, we investigated the effects of MMP-9 deletion on LV remodeling post-MI in aged mice. We enrolled 95 C57BL/6J (WT) and 91 MMP-9 null (null) mice of both sexes at 11 to 36 months of age, which in humans is the equivalent of 30 to 100 years of age. WT and null mice were analyzed at day 7 post-MI. The infarct area was similar (47±7% for WT and 46±6% for null; p=0.34) indicating equal initial ischemic stimuli. Post-MI, plasma MMP-9 levels were significantly increased and positively correlated with age in WT mice (r=0.46, p=0.001) but not null (r=0.08, p=0.11). Similar to young mice, MMP-9 deletion improved survival at day 7 post-MI (89% vs. 77% for WT, p=0.01). Regression analyses of LV function revealed that post-MI WT mice displayed U-shaped curves for end systolic and end diastolic dimensions. Of interest, the LV dilation response was lowest at 18 months of age, suggesting an optimum age between maturity and senescence. This effect was removed by MMP-9 deletion. Out of 84 genes measured, the inflammatory profile revealed an age-associated increase in 4 pro-inflammatory genes in WT (C3, CCl4, CX3CL1, and IL6ra- all p<0.05), while null mice showed increase in 2 pro-inflammatory genes (CCL5 and CXCL4- both p<0.05) and 7 anti-inflammatory genes (CCL1, CCL6, CCR1, IL11, IL1r2, IL8rb, and Mif- all p<0.05). At the isolated day 7 post-MI macrophage cellular level, MMP-9 deletion did not affect pro-inflammatory M1 macrophage polarization, but rather enhanced expression of anti-inflammatory M2 markers CD163, MRC1, TGF-β, and YM1 (all p<0.05). Combined, our findings demonstrate that MMP-9 deletion promotes anti-inflammatory polarization of macrophages to improve cardiac performance post-MI in the aging LV. The best age to have MI for mice was 18 months, which corresponds to 49 years in human.
This study is supported by HHSN 268201000036C (N01-HV-00244), HL095852, R01HL075360, HL051971, 5I01BX000505
Author Disclosures: A. Yabluchanskiy: None. Y. Ma: None. D. Bratton: None. Y.A. Chiao: None. A. Voorhees: None. H. Han: None. Y. Jin: None. M.L. Lindsey: None.
- © 2014 by American Heart Association, Inc.