Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction

The extent of cardiac remodeling determines survival after acute MI. However, the mechanisms driving cardiac remodeling remain unknown. We examined the effect of ischemia and reperfusion (R) on myocardial changes up to 6 days post-Ml. Pigs underwent 1.5 h or 4 h mid-LAD balloon occlusion and sacrificed or 1.5 h occlusion followed by R and sacrificed at 2.5 h, 1 day, 3 days, and 6 days. Ischemic- (IM) and non-ischemic myocardium (NIM) was obtained for molecular analysis of: 1) apoptosis (P-Bcl2, Bax, P-p53, active-caspase-3); 2) the TLR-4-MyD88-dependent and independent pathways; 3) Akt/mTOR/P70(S6K) axis activation; and, 4) fibrosis (TGF-beta, collagen1-A1/A3). Histopathology for inflammation, collagen, and fibroblast content, TUNEL staining, and metalloproteinase activity was performed. Apoptosis is only detected upon R in IM cardiomyocytes and progresses up to 6 days post-R mainly associated with infiltrated macrophages. The Akt/mTOR/P70(s6K) pathway is also activated upon R (IM) and remains elevated up to 6 days-R (P<0.05). Ischemia activates the TLR-4-MyD88-dependent (cytokines/chemokines) and -independent (IRF-3) pathways in IM and NIM and remains high up to 6 days post-R (P<0.05). Accordingly, leukocytes and macrophages are progressively recruited to the IM (P<0.05). Ischemia up-regulates pro-fibrotic TGF-beta that gradually rises collagen1-A1/-A3 mRNA with subsequent increase in total collagen fibrils and fibroblasts from 3 days-R onwards (P<0.005). MMP-2 activity increases from ischemia to 3 days post-R (P<0.05). We report that there is a timely coordinated cellular and molecular response to myocardial ischemia and R within the first 6 days after MI. In-depth understanding of the mechanisms involved in tissue repair is warranted to timely intervene and better define novel cardioprotective strategies. (C) 2011 Elsevier Ltd. All rights reserved.