title: The role of E2F-1 and downstream target genes in mediating ischemia/reperfusion injury in vivo.
abstract: E2Fs are a family of transcription factors that regulate proliferation, differentiation and apoptosis in many cell types. E2F-1 is the prototypical E2F and the family member that has most often been implicated in also mediating apoptosis. To better understand the role of E2F-1 in mediating cardiomyocyte injury we initially analyzed E2F family member expression after ischemia/reperfusion (I/R) in vivo or simulated ischemia in vitro. I/R injury in vivo caused a 3.4-fold increase specifically in E2F-1 protein levels. Expression of other E2F family members did not change. To establish the role of E2F-1 in I/R we examined the response of germline deleted E2F-1 mice to I/R injury. Infarct size as a percentage of the area at risk was decreased 39.8% in E2F-1(-/-) mice compared to E2F-1(+/+) controls. Interestingly, expression of classic, E2F-1 apoptotic target genes was not altered in E2F-1 null cardiomyocytes after I/R. However, upregulation of the primary member of the Forkhead family of transcription factors, FoxO-1a, was attenuated. Consistent, with a role for FoxO-1a as an important target of E2F-1 in I/R, a number of proapoptotic FoxO-1a target genes were also altered. These results suggest that E2F-1 and FoxO-1a belong to a complex transcriptional network that may modulate myocardial cell death during I/R injury.
authors.affiliation: Cardiovascular Research Laboratory, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Angelis
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Goldhaber
authors.forename: W Robb
authors.initials: WR
authors.lastname: Maclellan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
chemical_list: D050687:E2F1 Transcription Factor; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger