Abstract 868: Lack Of The Anti-inflammatory Lectin-like Domain Of Thrombomodulin Aggravates Dilatative Myocardial Remodelling Post-infarction And In Response To Increased Afterload
Introduction: Cardiac failure due to adverse myocardial remodelling is a frequent cause of cardiovascular morbidity and mortality. We have demonstrated that thrombomodulin (TM), through its anti-inflammatory lectin-like domain (LLD) is a powerful cardioprotective molecule, possibly by scavenging the pro-inflammatory cytokine HMGB-1. We hypothesized that via its role in inflammation, the LLD of TM may impact on myocardial remodelling. Using a knock-in mouse lacking the LLD of TM (TMLeD/LeD), we examined cardiac remodelling after myocardial infarction (MI) or left ventricular (LV) hypertrophy.
Methods: Wild-type (TMwt/wt) and TMLeD/LeD mice were subjected to transversal aortic constriction (TAC) with a gradient of 40±4 mm Hg or ligation of the LAD. Echocardiography was conducted before and 14 d after TAC or 4 d post-MI. Collagen expression (RT-PCR), myocyte area, leukocyte recruitment and collagen-1 deposition were analyzed. Non-parametric tests detected differences at p<0.05.
Results: MI induced more significant dilation in TMLeD/LeD- at day 4 compared to TMwt/wt-mice (post-MI-EDV: 60±5 vs 46±6 μl; ESV: 37±5 vs 22±4 μl; n=6, p<0.05). In the infarcted tissue, CD45+ leukocytes were increased 2.5-fold, collagen-1 mRNA 4.3-fold and collagen protein 1.3-fold after 7 d (p<0.05, n=6). In TMLeD/LeD mice subjected to TAC, LV mass (+15±3%, n=10, p<0.05) and myocyte area (+10±2%, n=6, p<0.05) increased significantly compared to TMwt/wt. By echocardiography, a 30±3% increase in LV-EDV was detected in TMLeD/LeD mice, while the LVs of TMwt/wt mice hypertrophied compared to baseline (−30±4% EDV, p<0.05, n=6). TMLeD/LeD subjected to TAC exhibited a 4.7-fold increase in CD45+ leukocytes (n=5, p<0.05), a 2.5-fold increase in collagen-1 mRNA levels (n=5, p<0.05), and a 1.3-fold increase in collagen-1 protein deposition at day 14 (p<0.05, n=5).
Discussion: Mice lacking the LLD of TM display dilatative maladaptive remodelling in response to infarction and afterload increases. Despite in the augmented collagen deposition, LV architecture appeared to be adversely affected by the pro-inflammatory effects of LLD deficiency. The TM/HMGB-1 axis promises to be a valuable therapeutic target to prevent adverse myocardial remodelling and consequent heart failure.