Kreipke R E, Birren S J
Department of Biology, National Center for Behavioral Genomics, Brandeis University, Waltham, MA, USA.
J Physiol. 2015 Dec 1;593(23):5057-73. doi: 10.1113/JP270917. Epub 2015 Nov 4.
Sympathetic drive to the heart is a key modulator of cardiac function and interactions between heart tissue and innervating sympathetic fibres are established early in development. Significant innervation takes place during postnatal heart development, a period when cardiomyocytes undergo a rapid transition from proliferative to hypertrophic growth. The question of whether these innervating sympathetic fibres play a role in regulating the modes of cardiomyocyte growth was investigated using 6-hydroxydopamine (6-OHDA) to abolish early sympathetic innervation of the heart. Postnatal chemical sympathectomy resulted in rats with smaller hearts, indicating that heart growth is regulated by innervating sympathetic fibres during the postnatal period. In vitro experiments showed that sympathetic interactions resulted in delays in markers of cardiomyocyte maturation, suggesting that changes in the timing of the transition from hyperplastic to hypertrophic growth of cardiomyocytes could underlie changes in heart size in the sympathectomized animals. There was also an increase in the expression of Meis1, which has been linked to cardiomyocyte cell cycle withdrawal, suggesting that sympathetic signalling suppresses cell cycle withdrawal. This signalling involves β-adrenergic activation, which was necessary for sympathetic regulation of cardiomyocyte proliferation and hypertrophy. The effect of β-adrenergic signalling on cardiomyocyte hypertrophy underwent a developmental transition. While young postnatal cardiomyocytes responded to isoproterenol (isoprenaline) with a decrease in cell size, mature cardiomyocytes showed an increase in cell size in response to the drug. Together, these results suggest that early sympathetic effects on proliferation modulate a key transition between proliferative and hypertrophic growth of the heart and contribute to the sympathetic regulation of adult heart size.
心脏的交感神经驱动是心脏功能的关键调节因子，心脏组织与支配性交感神经纤维之间的相互作用在发育早期就已建立。重要的神经支配发生在出生后心脏发育期间，这一时期心肌细胞经历从增殖性生长到肥大性生长的快速转变。使用6-羟基多巴胺（6-OHDA）消除心脏早期交感神经支配，研究了这些支配性交感神经纤维是否在调节心肌细胞生长模式中发挥作用。出生后化学性交感神经切除术导致大鼠心脏较小，表明在出生后期间心脏生长受支配性交感神经纤维调节。体外实验表明，交感神经相互作用导致心肌细胞成熟标志物延迟出现，这表明心肌细胞从增生性生长向肥大性生长转变时间的变化可能是去交感神经支配动物心脏大小变化的基础。Meis1的表达也增加了，这与心肌细胞退出细胞周期有关，表明交感神经信号抑制细胞周期退出。这种信号传导涉及β-肾上腺素能激活，这是交感神经调节心肌细胞增殖和肥大所必需的。β-肾上腺素能信号对心肌细胞肥大的影响经历了发育转变。虽然出生后早期的心肌细胞对异丙肾上腺素的反应是细胞大小减小，但成熟的心肌细胞对该药物的反应是细胞大小增加。总之，这些结果表明，早期交感神经对增殖的影响调节了心脏增殖性生长和肥大性生长之间的关键转变，并有助于对成年心脏大小的交感神经调节。
