The α1A/C- and α1B-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse
The α1A/C- and α1B-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse
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DOI：
10.1172/jci200316100
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发表时间：
2003-06-01
影响因子：
15.9
通讯作者：
Simpson, PC
中科院分区：
文献类型：
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作者：
O'Connell, TD;Ishizaka, S;Simpson, PC
儿茶酚胺和 α(1)-肾上腺素能受体 (α(1)-AR) 会导致培养的肌细胞和转基因小鼠心脏肥大，但在主要 α(1)-AR 亚型 α(1A/C) 和 α(1B) 的单一 KO 中，心脏大小正常。在这里，我们通过生成没有心脏 α(1)-AR 结合的 α(1A/C) 和 α(1B) 双 KO (ABKO) 小鼠来测试 α(1)-AR 是否是发育性心脏肥大所必需的。在雄性 ABKO 小鼠中，断奶后心脏生长比 WT 低 40%，心脏较小是由于心肌细胞较小。身体和其他器官的重量没有变化，表明对心脏有特定的影响。 ABKO 小鼠的血压与 WT 相同，表明心脏变小并不是由于负荷减少所致。通过超声心动图检查，清醒小鼠的收缩功能正常，但较小的心脏和较慢的心率会降低心输出量。 α(1)-AR 刺激不会激活 ABKO 肌细胞中的细胞外信号调节激酶 (Erk) 和下游激酶，并且完整 ABKO 心脏中的基础 Erk 活性较低。在雌性 ABKO 小鼠中，即使在卵巢切除术后，心脏大小也正常。雄性 ABKO 小鼠的运动能力因压力超负荷而降低，死亡率增加。因此，雄性小鼠的α(1)-AR是正常出生后心脏发育的生理肥大和对心脏应激的适应性反应所必需的。
Catecholamines and alpha(1)-adrenergic receptors (alpha(1)-ARs) cause cardiac hypertrophy in cultured myocytes and transgenic mice, but heart size is normal in single KOs of the main alpha(1)-AR subtypes, alpha(1A/C) and alpha(1B). Here we tested whether alpha(1)-ARs are required for developmental cardiac hypertrophy by generating alpha(1A/C) and alpha(1B) double KO (ABKO) mice, which had no cardiac alpha(1)-AR binding. In male ABKO mice, heart growth after weaning was 40% less than in WT, and the smaller heart was due to smaller myocytes. Body and other organ weights were unchanged, indicating a specific effect on the heart. Blood pressure in ABKO mice was the same as in WT, showing that the smaller heart was not due to decreased load. Contractile function was normal by echocardiography in awake mice, but the smaller heart and a slower heart rate reduced cardiac output. alpha(1)-AR stimulation did not activate extracellular signal-regulated kinase (Erk) and downstream kinases in ABKO myocytes, and basal Erk activity was lower in the intact ABKO heart. In female ABKO mice, heart size was normal, even after ovariectomy. Male ABKO mice had reduced exercise capacity and increased mortality with pressure overload. Thus, alpha(1)-ARs in male mice are required for the physiological hypertrophy of normal postnatal cardiac development and for an adaptive response to cardiac stress.