title: CHF1/Hey2 promotes physiological hypertrophy in response to pressure overload through selective repression and activation of specific transcriptional pathways.
abstract: We have previously found that CHF1/Hey2 prevents the development of phenylephrine-induced cardiac hypertrophy. To determine the role of CHF1/Hey2 in pressure overload hypertrophy, we performed ascending aortic banding on wild-type and transgenic mice overexpressing CHF1/Hey2 in the myocardium. We found that both wild-type and transgenic mice developed increased ventricular weight to body weight ratios 1 week after aortic banding. Wild-type mice also developed decreased fractional shortening after 1 week when compared to preoperative echocardiograms and sham-operated controls. Transgenic mice, in comparison, demonstrated preserved fractional shortening. Histological examination of explanted heart tissue demonstrated extensive fibrosis in wild-type hearts, but minimal fibrosis in transgenic hearts. TUNEL staining demonstrated increased apoptosis in the wild-type hearts but not in the transgenic hearts. Exposure of cultured neonatal myocytes from wild-type and transgenic animals to hydrogen peroxide, a potent inducer of apoptosis, demonstrated increased apoptosis in the wild-type cells. Gene Set Analysis of microarray data from wild-type and transgenic hearts 1 week after banding revealed suppression and activation of multiple pathways involving apoptosis, cell signaling, and biosynthesis. These findings demonstrate that CHF1/Hey2 promotes physiological over pathological hypertrophy through suppression of apoptosis and regulation of multiple transcriptional pathways. These findings also suggest that CHF1/Hey2 and its downstream pathways provide a variety of targets for novel heart failure drug discovery, and that genetic polymorphisms in CHF1/Hey2 may affect susceptibility to hypertrophy and heart failure.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Washington , Seattle, Washington, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Yu
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Liu
authors.forename: Fan
authors.initials: F
authors.lastname: Xiang
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Li
authors.forename: Darragh
authors.initials: D
authors.lastname: Cullen
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beyer
authors.forename: Theodor K
authors.initials: TK
authors.lastname: Bammler
authors.forename: Michael T
authors.initials: MT
authors.lastname: Chin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005355:Fibrosis / Q000473:pathology; D005786:Gene Expression Regulation; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C485778:Hey2 protein, mouse