Myofibroblast β2 adrenergic signaling amplifies cardiac hypertrophy in mice

被引:18
|
作者
Imaeda, Atsuki [1 ]
Tanaka, Shota [1 ]
Tonegawa, Kota [1 ]
Fuchigami, Shota [1 ]
Obana, Masanori [1 ]
Maeda, Makiko [2 ]
Kihara, Miho [3 ]
Kiyonari, Hiroshi [3 ,4 ]
Conway, Simon J. [5 ]
Fujio, Yasushi [1 ]
Nakayama, Hiroyuki [1 ]
机构
[1] Osaka Univ, Grad Sch Pharmaceut Sci, Lab Clin Sci & Biomed, Suita, Osaka, Japan
[2] Osaka Univ, Grad Sch Pharmaceut Sci, Educ & Res Unit Pharm D, Suita, Osaka, Japan
[3] Labs Anim Resource Dev, Kobe, Hyogo, Japan
[4] RIKEN Ctr Biosyst Dynam Res, Genet Engn, Kobe, Hyogo, Japan
[5] Indiana Univ Sch Med, Dept Pediat, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA
基金
美国国家卫生研究院;
关键词
Cardiac hypertrophy; Cardiac fibroblast; beta-adrenergic receptor; Paracrine effect; Protein kinase A; BETA(2)-ADRENERGIC RECEPTORS; RAT; INTERLEUKIN-6; FIBROBLAST; ACTIVATION; CELL; NOREPINEPHRINE; SURVIVAL; PATHWAYS;
D O I
10.1016/j.bbrc.2019.01.070
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Abnormal beta-adrenergic signaling plays a central role in human heart failure. In mice, chronic beta-adrenergic receptor (beta AR) stimulation elicits cardiac hypertrophy. It has been reported that cultured cardiac fibroblasts express beta AR; however, the functional in vivo requirement of beta AR signaling in cardiac fibroblasts during the development of cardiac hypertrophy remains elusive. beta 2AR null mice exhibited attenuated hypertrophic responses to chronic beta AR stimulation upon continuous infusion of an agonist, isoprenaline (ISO), compared to those in wildtype controls, suggesting that beta 2AR activation in the heart induces pro-hypertrophic effects in mice. Since beta 2AR signaling is protective in cardiomyocytes, we focused on beta 2AR signaling in cardiac myofibroblasts. To determine whether beta 2AR signaling in myofibroblasts affects cardiac hypertrophy, we generated myofibroblast-specific transgenic mice (TG) with the catalytic subunit of protein kinase A (PKAc alpha) using Cre-loxP system. Myofibroblast-specific PKAc alpha overexpression resulted in enhanced heart weight normalized to body weight ratio, associated with an enlargement of cardiomyocytes at 12 weeks of age, indicating that myofibroblast-specific activation of PKA mediates cardiac hypertrophy in mice. Neonatal rat cardiomyocytes stimulated with conditioned media from TG cardiac fibroblasts likewise exhibited significantly more growth than those from controls. Thus, beta 2AR signaling in myofibroblasts plays a substantial role in ISO-induced cardiac hypertrophy, possibly due to a paracrine effect. beta 2AR signaling in cardiac myofibroblasts may represent a promising target for development of novel therapies for cardiac hypertrophy. (C) 2019 Elsevier Inc. All rights reserved.
引用
收藏
页码:149 / 155
页数:7
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