Abstract 13284: Identification of a Unique Proteolytic-Profibrotic Interaction Following Myocardial Infarction Which is Amplified Following a Second Episode of Ischemia-Reperfusion
Objectives: A recognized structural event following a myocardial infarction (MI) is extracellular matrix (ECM) remodeling which includes induction of proteolytic pathways such as matrix metalloproteinases (MMPs, such as MMP-2 and MT1-MMP), and profibrotic pathways (i.e. transforming growth factor; TGF). However, how these pathways are evoked in the clinically relevant setting of a previous MI followed by a second episode of ischemia followed by reperfusion (I/R) remained unknown. This study tested the central hypothesis that unique and differential induction of proteolytic/profibrotic pathways would occur following I/R in the context of a previous MI.
Methods/Results: Pigs (35 kg) with a previous MI (3 wks post ligation of circumflex) or no MI were randomized to undergo I/R (60 min/120 min of left anterior descending occlusion) or no I/R as follows: no MI and no I/R (-MI,-I/R; n=6), no MI and I/R (-MI,+I/R; n=8), MI and no I/R (+MI,-I/R; n=8), MI and I/R (+MI,+I/R; n=8). LV regional shortening (sonomicrometry) was reduced by 50% in both I/R groups-consistent with myocardial stunning (p<0.05). A robust induction (mRNA levels by rtPCR) of MMP-2 and MT1-MMP occurred in the post-MI groups, which was accompanied by higher TGF receptor-1 levels (TGFR1) and the latency TGF binding protein (LTBP1), and collagen-3 levels (Table). Since LTBP1 regulates TGF release and binding to TGFR1, a validated, quenched fluorogenic substrate was used to directly measure MT1-MMP mediated LTBP1 activity, and was robustly increased in the +MI,+I/R group vs all other groups (1948±536 vs 851±275, 740±200, 700±172 ng/mg/hr, respectively, p<0.05).
Conclusions: These novel findings demonstrated an interaction between the proteolytic and profibrotic cascade (MT1-MMP mediated LTBP-1) occurs following MI, and a subsequent episode of I/R amplifies this interstitial proteolytic cascade within the MI region which can cause continued adverse remodeling.
- © 2010 by American Heart Association, Inc.