The NF-κB subunit c-Rel stimulates cardiac hypertrophy and fibrosis.
Cardiac remodeling and hypertrophy are the pathological consequences of cardiovascular disease and are correlated with its associated mortality. Activity of the transcription factor NF-κB is increased in the diseased heart; however, our present understanding of how the individual subunits contribute to cardiovascular disease is limited. We assign a new role for the c-Rel subunit as a stimulator of cardiac hypertrophy and fibrosis. We discovered that c-Rel-deficient mice have smaller hearts at birth, as well as during adulthood, and are protected from developing cardiac hypertrophy and fibrosis after chronic angiotensin infusion. Results of both gene expression and cross-linked chromatin immunoprecipitation assay analyses identified transcriptional activators of hypertrophy, myocyte enhancer family, Gata4, and Tbx proteins as Rel gene targets. We suggest that the p50 subunit could limit the prohypertrophic actions of c-Rel in the normal heart, because p50 overexpression in H9c2 cells repressed c-Rel levels and the absence of cardiac p50 was associated with increases in both c-Rel levels and cardiac hypertrophy. We report for the first time that c-Rel is highly expressed and confined to the nuclei of diseased adult human hearts but is restricted to the cytoplasm of normal cardiac tissues. We conclude that c-Rel-dependent signaling is critical for both cardiac remodeling and hypertrophy. Targeting its activities could offer a novel therapeutic strategy to limit the effects of cardiac disease.
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Silvia
S
Gaspar-Pereira
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Nicola
N
Fullard
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
Paul A
PA
Townsend
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Paul S
PS
Banks
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Elizabeth L
EL
Ellis
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Christopher
C
Fox
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Aidan G
AG
Maxwell
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Lindsay B
LB
Murphy
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
Adam
A
Kirk
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom.
Ralf
R
Bauer
Division of Immunity and Infection, Institute for BioMedical Research-Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham, United Kingdom.
Jorge H
JH
Caamaño
Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, University of Cambridge, Cambridge, United Kingdom.
Nichola
N
Figg
Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, University of Cambridge, Cambridge, United Kingdom.
Roger S
RS
Foo
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Jelena
J
Mann
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Derek A
DA
Mann
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address: fiona.oakley@ncl.ac.uk.
Fiona
F
Oakley
D000809:Angiotensins / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D016328:NF-kappa B / Q000502:physiology*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism / Q000502:physiology; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology
D000809:Angiotensins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel