Identification of IEX-1 as a biomechanically controlled nuclear factor-kappaB target gene that inhibits cardiomyocyte hypertrophy.
Biomechanical strain is a stimulus for cardiomyocyte hypertrophy and heart failure, but the underlying molecular mechanisms remain incompletely understood. Using an in vivo murine model of pressure overload and an in vitro model of mechanical stimulation of primary cardiomyocytes, we identified iex-1 as a gene activated during the early response of cardiomyocytes to hypertrophic stimuli and as a gene product that inhibits hypertrophy without affecting cardiomyocyte viability. On stimulation of cardiomyocytes, iex-1 mRNA and protein expression increased and translocation of the gene product to the cardiomyocyte nucleus occurred. iex-1 has previously been proposed as a mediator of NF-kappaB-dependent cell survival and growth in tumor cells. Here, we demonstrate that the biomechanical induction of iex-1 in cardiomyocytes was NF-kappaB-dependent, as overexpression of the NF-kappaB inhibitor IkappaBalpha completely inhibited strain-mediated iex-1 mRNA accumulation. The functional role of iex-1 was investigated by overexpressing wild-type iex-1 with replication-defective adenoviral gene transfer. Overexpression of iex-1 abolished cardiomyocyte hypertrophy by mechanical strain, phenylephrine, or endothelin-1 at levels that did not affect cell viability. These studies identify iex-1 as a biomechanical stress-inducible and NF-kappaB-dependent gene in cardiac muscle cells during the acute phase of hypertrophy with negative growth regulatory effects that may counterbalance early hypertrophic responses in activated cardiomyocytes.
De Keulenaer
Gilles W
GW
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Massachusetts, USA.
Wang
Yanlin
Y
Feng
Yajun
Y
Muangman
Suphi
S
Yamamoto
Keiji
K
Thompson
John F
JF
Turi
Thomas G
TG
Landschutz
Katherine
K
Lee
Richard T
RT
D000256:Adenoviridae; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D048429:Cell Size / Q000235:genetics; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins; D016328:NF-kappa B / Q000235:genetics*; D009363:Neoplasm Proteins; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; C099815:IER3 protein, human; D017874:Immediate-Early Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger