Critical Roles for the Fas/Fas Ligand System in Postinfarction Ventricular Remodeling and Heart Failure

Abstract

Abstract-In myocardial infarction (MI), granulation tissue cells disappear via apoptosis to complete a final scarring with scanty cells. Blockade of this apoptosis was reported to improve post-MI ventricular remodeling and heart failure. However, the molecular biological mechanisms for the apoptosis are unknown. Fas and Fas ligand were overexpressed in the granulation tissue at the subacute stage of MI (1 week after MI) in mice, where apoptosis frequently occurred. In mice lacking functioning Fas (lpr strain) and in those lacking Fas ligand (gld strain), apoptotic rate of granulation tissue cells was significantly fewer compared with that of genetically controlled mice, and post-MI ventricular remodeling and dysfunction were greatly attenuated. Mice were transfected with adenovirus encoding soluble Fas (sFas), a competitive inhibitor of Fas ligand, on the third day of MI. The treatment resulted in suppression of granulation tissue cell apoptosis and produced a thick, cell-rich infarct scar containing rich vessels and bundles of smooth muscle cells with a contractile phenotype at the chronic stage (4 weeks after MI). This accompanied not only alleviation of heart failure but also survival improvement. However, the sFas gene delivery during scar tissue phase was ineffective, suggesting that beneficial effects of the sFas gene therapy owes to inhibition of granulation tissue cell apoptosis. The Fas/Fas ligand interaction plays a critical role for granulation tissue cell apoptosis after MI. Blockade of this apoptosis by interfering with the Fas/Fas ligand interaction may become one of the therapeutic strategies against chronic heart failure after large MI.

Postinfarction Gene Therapy Against Transforming Growth Factor-β Signal Modulates Infarct Tissue Dynamics and Attenuates Left Ventricular Remodeling and Heart Failure

“…23,24 Recently, we reported that blockade of myofibroblast apoptosis by the treatment with pan-caspase inhibitor or with soluble Fas, a competitive inhibitor of Fas, attenuates postinfarction ventricular remodeling and heart failure. 25,26 We speculate that the preserved myofibroblasts may contribute structurally to the thickening of the infarct scar. In addition, although the property of contractile function of these myofibroblasts has not been elucidated, it is conceivable that contractile myofibroblasts that are running parallel with the infarct circumference may shrink the infarct into coronal directions and increase the infarct thickness.…”

Rodent models of heart failure: an updated review

“…Surviving mice gradually develop HF within the 4 weeks following the surgical procedure [76,155,158]. In rats, a significant decrease up to 25% in cardiac output is observed 8 weeks after LAD ligation [115].…”

Elevation of Plasma Granzyme B Levels After Acute Myocardial Infarction

“…13,14 Granulation tissue formed after myocardial infarction (MI) contains chronic inflammatory cells, and in recent studies, the activated Fas/FasL system and elevated levels of TNF-α released from inflammatory cells contributed to LV remodeling after AMI. 15,16 Interestingly, in our previous report we suggested that granzyme B plays an important role in triggering ACS by degrading coronary plaques, 17 amd we hypothesized that apoptosis-related molecules contribute to LV remodeling after AMI by inducing apoptosis and matrix degradation. In the present study, we focused on the role of granzyme B in LV remodeling after AMI.…”