Abstract P146: Fas-ligand Induces Cardiomyopathy via the Activation of the Erk1/2 Pathway
Fas receptor and its ligand, Fas-L, are the most well characterized co-stimulatory molecules playing an essential role in the induction of programmed cell death or apoptosis. Increase of circulating Fas-L in serum and in cardiomyocytes are described in different models of cardiac diseases such as myocarditis, pressure overload, AND myocardial infarction/ischemia. In addition, associated activation of inflammatory pathwayshas been observed. However, no studies have yet revealed mechanisms underlying the pathogenecity of FasL in the heart.
Transgenic mice (C57/Bl6) with cardiac-specific over-expression of Fas-L were investigated. We characterized cardiac function by echocardiography. Cellular and molecular studies were performed on heart tissue using genomic, histologic, immunological, and protein analysis techniques.
Fas-L transgenic mice had a significant rate of mortality (p<0.0001) compared to WT due to heart failure. Histological studies of Fas-L hearts revealed predominant perivascular fibrosis associated with inflammation. Expression studies of secondary messengers of the activated Fas/FasL system demonstrated up-regulation of an active CASP-3 confirming induction of apoptosis in myocardium. Down-regulation of FLIP, NIK and NF-κB was evident. Interestingly, RIP was up-regulated leading to the activation of ERK1/2 (4.27±0.158 vs 10.086±1.591 in WT and FasL mice hearts, respectively, p=0.022). Analysis of inflammatory mediators revealed increase in secretion of interleukines (IL-17, IL-6, IL-1β and TNF-α) and diffuse infiltration of CD3 positive cells. Studies of fibrotic pathways showed an increased expression of periostin and osteopontin, but not activation of TGFβ1, showing that periostin and osteopontin can be activated independently of TGFβ1 via the ERK1/2 pathway,
Our findings suggest that Fas-L induces cardiac failure, via an activation of the ERK1/2 pathway, which is an important player involved in the hypertrophic response in the heart. Targeting the ERK1/2 pathway in cardiac diseases associated with Fas-L expression may therefore be able to prevent progression to cardiomyopathy.
- © 2011 by American Heart Association, Inc.