title: Expression of FAS adjacent to fibrotic foci in the failing human heart is not associated with increased apoptosis.
abstract: Fibrosis in the heart may result from loss of myocytes, which are replaced by collagens. Apoptosis is now known to contribute to myocyte loss in the failing human heart. The mechanisms underlying the induction of cardiomyocyte apoptosis, and thus the expansion of fibrotic foci in the failing heart, are poorly understood. We hypothesized that viable heart cells adjacent to fibrotic foci might become "predisposed" to apoptosis by expression of the receptor FAS (APO1, CD95). We therefore studied the spatial relationship of FAS expression and fibrosis in patients with heart failure. Left ventricular biopsies were obtained from seven patients undergoing coronary artery bypass grafting. All patients had reduced ejection fraction but varied in New York Heart Association class score at the time of surgery. Heart cell apoptosis, fibrosis, and FAS expression were studied by propidium iodide and in situ end labeling (ISEL) of DNA, Picrosirius red staining, and immunohistochemistry. All patient samples exhibited, albeit to varying degrees, apoptosis detected by ISEL, chromatin condensation, and nuclear fragmentation. In all samples, fibrosis (collagen) was evident both perivascular and in isolated regions of scarring. Regardless of the extent of fibrosis or detectable apoptosis, FAS expression was observed in regions immediately adjacent to the fibrosis, but not in regions distal to fibrosis, nor in fibrotic areas devoid of nuclei. Expression of FAS was found adjacent to both perivascular and diffuse fibrosis, and ISEL-positive nuclei were found within cells reacting positively with anti-FAS antibodies. However, ISEL-positive nuclei were no more abundant in FAS-positive regions (67.6 +/- 5.8% of total nuclei) than in FAS-negative areas (69.5 +/- 9.8%). We conclude that expression of FAS occurs in remaining heart cells adjacent to fibrosis of either perivascular or presumed reparative origin. Although this phenomenon could contribute to the expansion of fibrotic foci, FAS-induced apoptosis in the failing heart may not be more prevalent than apoptosis initiated by other signaling mechanisms.
authors.affiliation: The Cardiovascular Institute, Michael Reese Hospital and Medical Center, Chicago, Illinois 60616; and Evangelismos General Hospital, Athens 10676, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Filippatos
authors.forename: C
authors.initials: C
authors.lastname: Leche
authors.forename: R
authors.initials: R
authors.lastname: Sunga
authors.forename: A
authors.initials: A
authors.lastname: Tsoukas
authors.forename: P
authors.initials: P
authors.lastname: Anthopoulos
authors.forename: I
authors.initials: I
authors.lastname: Joshi
authors.forename: A
authors.initials: A
authors.lastname: Bifero
authors.forename: R
authors.initials: R
authors.lastname: Pick
authors.forename: B D
authors.initials: BD
authors.lastname: Uhal
mesh_terms: D000368:Aged; D017209:Apoptosis; D001706:Biopsy; D002303:Cardiac Output, Low / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D020401:Primed In Situ Labeling; D014018:Tissue Distribution; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D019014:fas Receptor