Changes in adenylyl cyclase isoforms as a mechanism for thyroid hormone modulation of cardiac beta-adrenergic receptor responsiveness.
Changes in adenylyl cyclase isoforms as a mechanism for thyroid hormone modulation of cardiac beta-adrenergic receptor responsiveness.
复制标题
腺苷酸环化酶亚型的变化作为甲状腺激素调节心脏β-肾上腺素能受体反应性的机制。
DOI：
10.1016/s0026-0495(00)92262-5
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Steinberg,SF
中科院分区：
文献类型：
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作者：
Ojamaa,K;Klein,I;Sabet,A;Steinberg,SF
虽然已知甲状腺激素可以调节心脏β-肾上腺素能受体的表达，但这些变化在甲状腺激素代谢改变的心脏表现中的生理意义一直存在争议。本研究探讨了甲状腺激素是否通过调节心脏腺苷酸环化酶（AC）异构体表达，通过环磷酸腺苷（cAMP）途径调节信号。对甲状腺功能低下、甲状腺功能正常和甲状腺功能亢进的大鼠脑室进行Northern blot分析和AC酶测定。甲状腺功能减退室心脏AC mRNA V、VI稳态水平分别为甲状腺功能正常室的173%±8%和149%±12% （P < 0.01）。在AC mRNA亚型增加的同时，forskolin和Mn对催化AC的激活也增加了1.5倍（P < 0.05）。相比之下，V型和VI型AC转录本的相对丰度在甲状腺功能亢进和甲状腺功能正常的脑室中相似，但在甲状腺功能亢进脑室的膜中，福斯olin和Mn对AC的催化活性显著降低了35%。异丙肾上腺素刺激β-肾上腺素能受体的AC激活不受甲状腺激素状态的影响。因此，甲状腺激素抑制AC催化活性的作用有望抵消甲状腺机能亢进中β-肾上腺素能受体表达的增加。这些研究确定了心脏AC酶是通过cAMP途径进行甲状腺激素依赖性信号调节的重要靶点，并支持了心脏肾上腺素能反应性在甲状腺疾病状态下不变的发现。
Although thyroid hormones are known to modulate cardiac β-adrenergic receptor expression, the physiologic implications of these changes in the cardiac manifestations of altered thyroid hormone metabolism have been disputed. This study examined whether thyroid hormone modulates signaling via the cyclic adenosine monophosphate (cAMP) pathway by regulating cardiac adenylyl cyclase (AC) isoform expression. Northern blot analyses and AC enzyme assays were performed on preparations ffrom hypothyroid, euthyroid, and hyperthyroid rat ventricles. Steady-state levels of cardiac AC mRNA types V and VI in hypothyroid ventricles were 173% ± 8% and 149% ± 12%, respectively, of the values in euthyroid ventricles (P < .01). This increase in AC mRNA isoforms was accompanied by a 1.5-fold increase (P < .05) in the activation of catalytic AC by forskolin and Mn. In contrast, the relative abundance of transcripts for types V and VI AC was similar in hyperthyroid and euthyroid ventricles, but catalytic AC activation by forskolin and Mn was significantly reduced by 35% in membrane obtained from hyperthyroid ventricles. AC activation through β-adrenergic receptor stimulation by isoproterenol was not altered by thyroid hormone status. Thus, the effect of thyroid hormone to repress AC catalytic activity would be anticipated to offset the increase in β-adrenergic receptor expression in hyperthyroidism. These studies identify cardiac AC enzymes as important targets for thyroid hormone—dependent regulation of signaling via the cAMP pathway, and support the finding that cardiac adrenergic responsiveness is unaltered in thyroid disease states.