Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados, del Instituto Politécnico Nacional, México, DF, México.
J Cardiovasc Pharmacol. 2011 Nov;58(5):470-8. doi: 10.1097/FJC.0b013e31822a789b.
The effects of long-term β-adrenergic administration on the expression levels of the cardiac L-type Ca channel β2 subunit, which regulates channel trafficking and function, were characterized in adult rats.
Systemic administration of isoproterenol (150 mg·kg·h) for 2 d led to a 50% increase in the ventricular wet weight-to-body weight ratio (mg/g) and of more than two-fold in the expression of actin protein. In contrast, β2 subunit protein levels decreased (down to 49%), while mRNA levels remained unchanged. Furthermore, levels of microRNAs (miRs), including miR-21 and miR-132, were upregulated (7.2 and 7.9 fold, respectively). Transfection of these miRs into HEK293 cells attenuated expression of a luciferase reporter gene controlled by a conserved 3'-untranslated region (UTR) of the β2 subunit (down to 67% and 56%, respectively). Systemic administration of isoproterenol also led to briefer intracellular Ca transients during action potentials measured in isolated cardiomyocytes (down to 65%).
These results suggest that cardiac L-type Ca channel β2 subunit protein expression may be downregulated by miRs in response to long-term activation of β-adrenergic signaling, possibly as an adaptive response in cardiac hypertrophy and sustained β-adrenergic states.
本研究旨在探讨长期β肾上腺素能刺激对心脏 L 型钙通道β2 亚基表达水平的影响，该亚基调节通道运输和功能。
连续 2 天给予异丙肾上腺素（150mg·kg·h）可使心室湿重/体重比值增加 50%，肌动蛋白蛋白表达增加两倍以上。相比之下，β2 亚基蛋白水平下降（降至 49%），而 mRNA 水平保持不变。此外，microRNAs（miRs），包括 miR-21 和 miR-132，表达上调（分别上调 7.2 倍和 7.9 倍）。将这些 miR 转染到 HEK293 细胞中，可使受β2 亚基保守 3'非翻译区（UTR）控制的荧光素酶报告基因的表达降低（分别降至 67%和 56%）。异丙肾上腺素的全身给药也导致在分离的心肌细胞中动作电位期间细胞内 Ca 瞬变短暂（降至 65%）。
这些结果表明，心脏 L 型钙通道β2 亚基蛋白表达可能受 miRs 下调，以响应β肾上腺素能信号的长期激活，这可能是心脏肥大和持续β肾上腺素能状态的一种适应性反应。
