Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, Freiburg, Germany.
Basic Res Cardiol. 2011 Jun;106(4):591-602. doi: 10.1007/s00395-011-0166-z. Epub 2011 Mar 10.
Increased activity of the sympathetic system is an important feature contributing to the pathogenesis and progression of chronic heart failure. While the mechanisms and consequences of enhanced norepinephrine release from sympathetic nerves have been intensely studied, the role of the adrenal gland in the development of cardiac hypertrophy and progression of heart failure is less well known. Thus, the aim of the present study was to determine the effect of chronic cardiac pressure overload in mice on adrenal medulla structure and function. Cardiac hypertrophy was induced in wild-type mice by transverse aortic constriction (TAC) for 8 weeks. After TAC, the degree of cardiac hypertrophy correlated significantly with adrenal weight and adrenal catecholamine storage. In the medulla, TAC caused an increase in chromaffin cell size but did not result in chromaffin cell proliferation. Ablation of chromaffin α(2C)-adrenoceptors did not affect adrenal weight or epinephrine synthesis. However, unilateral denervation of the adrenal gland completely prevented adrenal hypertrophy and increased catecholamine synthesis. Transcriptome analysis of microdissected adrenal medulla identified 483 up- and 231 downregulated, well-annotated genes after TAC. Among these genes, G protein-coupled receptor kinases 2 (Grk2) and 6 and phenylethanolamine N-methyltransferase (Pnmt) were significantly upregulated by TAC. In vitro, acetylcholine-induced Pnmt and Grk2 expression as well as enhanced epinephrine content was prevented by inhibition of nicotinic acetylcholine receptors and Ca(2+)/calmodulin-dependent signaling. Thus, activation of preganglionic sympathetic nerves innervating the adrenal medulla plays an essential role in inducing adrenal hypertrophy, enhanced catecholamine synthesis and induction of Grk2 expression after cardiac pressure overload.
交感神经系统活性增加是导致慢性心力衰竭发病和进展的重要特征。虽然交感神经去甲肾上腺素释放的机制和后果已经得到了深入研究，但肾上腺在心脏肥大发展和心力衰竭进展中的作用知之甚少。因此，本研究旨在确定慢性心脏压力超负荷对小鼠肾上腺髓质结构和功能的影响。通过横主动脉缩窄（TAC）在野生型小鼠中诱导心脏肥大 8 周。TAC 后，心脏肥大的程度与肾上腺重量和肾上腺儿茶酚胺储存呈显著正相关。在髓质中，TAC 导致嗜铬细胞大小增加，但不会导致嗜铬细胞增殖。破坏嗜铬细胞 α(2C)-肾上腺素能受体不会影响肾上腺重量或肾上腺素合成。然而，单侧肾上腺去神经支配完全防止了肾上腺肥大和增加儿茶酚胺合成。对微分离的肾上腺髓质进行转录组分析，发现 TAC 后有 483 个上调和 231 个下调的、注释良好的基因。在这些基因中，G 蛋白偶联受体激酶 2（Grk2）和 6 和苯乙醇胺 N-甲基转移酶（Pnmt）被 TAC 显著上调。在体外，乙酰胆碱诱导的 Pnmt 和 Grk2 表达以及增强的肾上腺素含量被烟碱型乙酰胆碱受体和 Ca(2+)/钙调蛋白依赖性信号的抑制所阻止。因此，支配肾上腺髓质的节前交感神经的激活在心脏压力超负荷后诱导肾上腺肥大、增强儿茶酚胺合成和诱导 Grk2 表达中起重要作用。
