Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis
Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis
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DOI：
10.1074/jbc.m411694200
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发表时间：
2005-08-19
影响因子：
4.8
通讯作者：
Matsumoto, T
中科院分区：
文献类型：
--
作者：
Ikeda, Y;Aihara, K;Matsumoto, T
雄激素对心肌细胞具有合成代谢作用，并已被证明可增强左心室扩大和功能。然而，雄激素在心脏生长和心脏应激诱导的重塑中的生理和病理生理作用仍不清楚。我们的目的是澄清雄激素核雄激素受体（AR）系统是否有助于心脏的生长和血管紧张素II（Ang II）刺激的心脏重塑，通过使用全身性AR基因敲除雄性小鼠。AR敲除（ARKO）雄性小鼠，在25周龄时，和年龄匹配的野生型（WT）雄性小鼠用或不用Ang II刺激（2.0 mg/kg/天）处理2周。与WT小鼠相比，有或没有Ang II刺激的ARKO小鼠的心脏与体重比显着降低。此外，超声心动图分析表明，在血管紧张素II刺激的ARKO小鼠的向心性肥厚反应和左心室功能的损害。心肌的Western印迹分析显示，ARKO小鼠中由Ang II刺激引起的细胞外信号调节激酶（ERK）1/2和ERK 5的激活低于WT小鼠。Ang II刺激在ARKO小鼠中引起的心脏纤维化比WT小鼠更突出，I型和III型胶原蛋白和转化生长因子β 1基因的表达增强，Smad 2活化增加。这些结果表明，在雄性小鼠中，雄激素-AR系统参与正常的心脏生长，并在肥大应激下的心脏重塑过程中调节心脏适应性肥大和纤维化。
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-beta 1 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.