title: Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis.
abstract: Androgen has anabolic effects on cardiac myocytes and has been shown to enhance left ventricular enlargement and function. However, the physiological and patho-physiological roles of androgen in cardiac growth and cardiac stress-induced remodeling remains unclear. We aimed to clarify whether the androgen-nuclear androgen receptor (AR) system contributes to the cardiac growth and angiotensin II (Ang II)-stimulated cardiac remodeling by using systemic AR-null male mice. AR knock-out (ARKO) male mice, at 25 weeks of age, and age-matched wild-type (WT) male mice were treated with or without Ang II stimulation (2.0 mg/kg/day) for 2 weeks. ARKO mice with or without Ang II stimulation showed a significant reduction in the heart-to-body weight ratio compared with those of WT mice. In addition, echocardiographic analysis demonstrated impairments of both the concentric hypertrophic response and left ventricular function in Ang II-stimulated ARKO mice. Western blot analysis of the myocardium revealed that activation of extracellular signal-regulated kinases (ERK) 1/2 and ERK5 by Ang II stimulation were lower in ARKO mice than those of WT mice. Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-beta1 genes and with increased Smad2 activation. These results suggest that, in male mice, the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during the process of cardiac remodeling under hypertrophic stress.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Aihara
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Masashi
authors.initials: M
authors.lastname: Akaike
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshizumi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Suzaki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Izawa
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Fujimura
authors.forename: Shunji
authors.initials: S
authors.lastname: Hashizume
authors.forename: Midori
authors.initials: M
authors.lastname: Kato
authors.forename: Shusuke
authors.initials: S
authors.lastname: Yagi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kawano
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Azuma
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000209:etiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005355:Fibrosis; D006339:Heart Rate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D009206:Myocardium / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D020257:Ventricular Remodeling
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7