title: Myocardin-related transcription factor A is a common mediator of mechanical stress- and neurohumoral stimulation-induced cardiac hypertrophic signaling leading to activation of brain natriuretic peptide gene expression.
abstract: Subjecting cardiomyocytes to mechanical stress or neurohumoral stimulation causes cardiac hypertrophy characterized in part by reactivation of the fetal cardiac gene program. Here we demonstrate a new common mechanism by which these stimuli are transduced to a signal activating the hypertrophic gene program. Mechanically stretching cardiomyocytes induced nuclear accumulation of myocardin-related transcription factor A (MRTF-A), a coactivator of serum response factor (SRF), in a Rho- and actin dynamics-dependent manner. Expression of brain natriuretic peptide (BNP) and other SRF-dependent fetal cardiac genes in response to acute mechanical stress was blunted in mice lacking MRTF-A. Hypertrophic responses to chronic pressure overload were also significantly attenuated in mice lacking MRTF-A. Mutation of a newly identified, conserved and functional SRF-binding site within the BNP promoter, or knockdown of MRTF-A, reduced the responsiveness of the BNP promoter to mechanical stretch. Nuclear translocation of MRTF-A was also involved in endothelin-1- and angiotensin-II-induced activation of the BNP promoter. Moreover, mice lacking MRTF-A showed significantly weaker hypertrophic responses to chronic angiotensin II infusion than wild-type mice. Collectively, these findings point to nuclear translocation of MRTF-A as a novel signaling mechanism mediating both mechanical stretch- and neurohumoral stimulation-induced BNP gene expression and hypertrophic responses in cardiac myocytes.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan. kuwa@kuhp.kyoto-u.ac.jp
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuwabara
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Usami
authors.forename: Takeya
authors.initials: T
authors.lastname: Minami
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Masataka
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D051381:Rats; D026362:Serum Response Factor / Q000378:metabolism; D013314:Stress, Mechanical; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000099251:Myocardin
chemical_list: D000804:Angiotensin II; D019332:Endothelin-1; D020097:Natriuretic Peptide, Brain; D009687:Nuclear Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; D000099251:Myocardin; C511173:Mrtfa protein, mouse