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Heterogeneity in MT1-MMP activity with ischemia-reperfusion and previous myocardial infarction: relation to regional
Jennifer A Dixon1, William F Gaillard, William T Rivers
1Division of Cardiothoracic Surgery, Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA.
Abstract:
After a myocardial infarction (MI), an episode of ischemia-reperfusion (I/R) can result in a greater impairment of left ventricular (LV) regional function (LVRF) than that caused by an initial I/R episode in the absence of MI. Membrane type-I matrix metalloproteinase (MT1-MMP) proteolytically processes the myocardial matrix and is upregulated in LV failure. This study tested the central hypothesis that a differential induction of MT1-MMP occurs and is related to LVRF after I/R in the context of a previous MI. Pigs with a previous MI [3 wk postligation of the left circumflex artery (LCx)] or no MI were randomized to undergo I/R [60-min/120-min left anterior descending coronary artery (LAD) occlusion] or no I/R as follows: no MI and no I/R (n = 6), no MI and I/R (n = 8), MI and no I/R (n = 8), and MI and I/R (n = 8). Baseline LVRF (regional stroke work, sonomicrometry) was lower in the LAD region in the MI group compared with no MI (103 ± 12 vs. 188 ± 26 mmHg·mm, P < 0.05) and remained lower with peak ischemia (35 ± 8 vs. 88 ± 17 mmHg·mm, P < 0.05). Using a novel interstitial microdialysis method, MT1-MMP was directly measured and was over threefold higher in the LCx region and over twofold higher in the LAD region in the MI group compared with the no MI group at baseline. MT1-MMP fluorogenic activity was persistently elevated in the LCx region in the MI and I/R group but remained unchanged in the LAD region. In contrast, no changes in MT1-MMP occurred in the LCx region in the no MI and I/R group but increased in the LAD region. MT1-MMP mRNA was increased by over threefold in the MI region in the MI and I/R group. In conclusion, these findings demonstrate that a heterogeneous response in MT1-MMP activity likely contributes to regional dysfunction with I/R and that a subsequent episode of I/R activates a proteolytic cascade within the MI region that may contribute to a continued adverse remodeling process.
Insights
A previous myocardial infarction (MI) leads to greater heart dysfunction after ischemia-reperfusion (I/R). This is linked to differential matrix metalloproteinase (MT1-MMP) activity, suggesting a role in adverse cardiac remodeling.
Area of Science:
- Cardiovascular Physiology
- Cardiac Remodeling
- Matrix Biology
Background:
- Myocardial infarction (MI) can lead to impaired left ventricular regional function (LVRF).
- Ischemia-reperfusion (I/R) injury following MI exacerbates LVRF compared to I/R without prior MI.
- Membrane type-I matrix metalloproteinase (MT1-MMP) is involved in myocardial matrix remodeling and is upregulated in heart failure.
Purpose of the Study:
- To investigate the hypothesis that differential induction of MT1-MMP occurs and relates to LVRF after I/R in the context of a previous MI.
- To assess the impact of a prior MI on MT1-MMP expression and activity during a subsequent I/R event.
Main Methods:
- Pigs with or without a previous MI were subjected to I/R or no I/R.
- Left ventricular regional function (LVRF) was assessed using sonomicrometry.
- Interstitial MT1-MMP levels were measured using a novel microdialysis technique.
- MT1-MMP mRNA expression was analyzed in myocardial tissue.
Main Results:
- Baseline LVRF was significantly lower in pigs with prior MI.
- MT1-MMP levels were elevated at baseline in both regions of the myocardium in pigs with prior MI.
- Following I/R, MT1-MMP activity was persistently elevated in the previously infarcted region but increased in the non-infarcted region.
- MT1-MMP mRNA was significantly upregulated in the MI region after I/R.
Conclusions:
- Heterogeneous MT1-MMP activity contributes to regional dysfunction following I/R in the setting of prior MI.
- Subsequent I/R activates a proteolytic cascade within the infarcted region.
- This cascade may promote continued adverse cardiac remodeling post-MI.
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