Abstract 864: Fibulin-2 Deficiency Improves Survival After Experimental Myocardial Infarction by Attenuating Myocardial Fibrosis and Ventricualar Dysfunction
Background: Ventricular myocardium undergoes geometric changes as physiological adaptation, but the regulatory mechanisms governing the transition from this compensatory adaptation to heart failure are not well understood. We recently found that fibulin-2, an extracellular matrix (ECM) protein, promotes reparative fibrosis after myocardial infarction (MI) in the mouse model. Here we examined whether fibulin-2 is involved in progression of chronic reactive fibrosis after MI.
Materials and Methods: Fibulin-2 total deficient mice (Fbln2−/−) and age matched wild type (WT) male mice were studied and their left anterior descending coronary artery was ligated near its origin to produce a large MI. Ventricular function was assessed by echocardiography and cardiac catheterization. Tissues from non-ischemic myocardium were collected 2 weeks after MI for real-time RT-PCR, Western blot, gelatin zymography, and histology. Data are expressed as mean ± SEM.
Results: Two weeks following large MI (approximately 50% of LV subjected to permanent ischemia), survival rate was significantly better in Fbln2−/− than in WT (85 vs. 45%; n = 60 and 73, respectively). Ventricular hypertrophy and dilatation were comparable between the two groups. However, Fbln2−/− showed significantly better ventricular function than WT by echocardiogram (%FS 34.6 ± 1.2 vs. 27 ± 2.1%, p< 0.01) and by hemodynamic assessment [LVEDP 8.5 ± 1.4 vs. 20.1 ± 2.2 mmHg, p < 0.005; (+)dP/dTmax 4885 ±392 vs. 3055 ±591 mmHg/s, p< 0.05; and (−)dP/dTmax 4102±308 vs. 2437 ±419 mmHg/s, p< 0.005]. Collagens type I, type III, and MMP-2 mRNA expressions were significantly higher in WT than in Fbln2−/−, as were the histological evidence of myocardial fibrosis and MMP-2 activity. TGF-β1 and its phosphorylated downstream signaling proteins, p-Smad2, p-TAK-1, and p-p38, were all significantly up-regulated in WT but not in Fbln2−/−.
Conclusion: Deficiency of fibulin-2 does not prevent ventricular dilatation or hypertrophy after large transmural MI but dramatically improves survival and ventricular function by attenuating myocardial fibrosis. Our data suggest that fibuiln-2 modulates TGF-β in provoking myocardial fibrosis after MI and thus may play a pivotal role in the progression of post-MI heart failure.