Dorn Gerald W
Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0542, USA.
J Card Fail. 2002 Dec;8(6 Suppl):S370-3. doi: 10.1054/jcaf.2002.129267.
Cardiac insufficiency, acute or chronic, engenders an increase in systemic and local myocardial sympathetic tone with release of the endogenous sympathetic hormones epinephrine and norepinephrine. These catecholamines activate cardiomyocyte alpha- and beta-adrenergic receptors which, although responsive to the same hormonal ligands, stimulate almost entirely distinct signaling pathways with different end organ results.
Minute-by-minute cardiac function is regulated by the beta-adrenergic receptor system, coupled to the adenylate cyclase and protein kinase (PK) A pathway via the Gs heterotrimeric G protein. In contrast, activation of alpha-adrenergic receptors and the Gq/phospholipase C/PKC pathway has little acute effect on instantaneous myocardial contractility, but can be a potent stimulus for cardiac hypertrophy.
The distinct effects of alpha- and beta-adrenergic pathways in the in vivo heart, which are difficult to dissociate using conventional pharmacologic techniques, have been delineated through the use of cardiac-specific transgenic overexpression of individual components of their respective signaling pathways. Ventricular remodeling resulting from overexpression of alpha-adrenergic receptors or the alpha subunit of the Gq heterotrimeric G protein takes the form of concentric or eccentric hypertrophy without ventricular dilation or myocardial fibrosis. Cardiomyocyte cell size is increased and a panel of hypertrophy-associated embryonic cardiac genes is reexpressed. These phenotypic features are characteristic of pressure overload hypertrophy, and inhibition of Gq signaling can, in fact, prevent pressure overload hypertrophy in mice. Increased signaling through Gq exceeding that which causes hypertrophy results in cardiomyocyte apoptosis and progression from compensated hypertrophy to dilated cardiomyopathy.
Transgenic overexpression of beta-adrenergic receptors or the alpha subunit of the Gs heterotrimeric G protein results in the expected increase in myocardial contractility, but also causes a progressive cardiomyocyte loss resulting in a delayed fibrotic cardiomyopathy, thus recapitulating the clinical syndrome of catecholamine cardiomyopathy as seen with pheochromocytoma or iatrogenic catecholamine infusion. These effects of beta-adrenergic receptors are concentration-dependent, and appear to be much more severe for the beta 1 than the beta 2 subtype, perhaps because of beta 2 coupling to inhibitory Gi.
急慢性心功能不全可导致全身及局部心肌交感神经张力增加，内源性交感激素肾上腺素和去甲肾上腺素释放。这些儿茶酚胺激活心肌细胞α和β肾上腺素能受体，尽管它们对相同的激素配体有反应，但几乎完全刺激不同的信号通路，产生不同的终末器官效应。
每分钟的心脏功能由β肾上腺素能受体系统调节，该系统通过Gs异源三聚体G蛋白与腺苷酸环化酶和蛋白激酶（PK）A途径偶联。相反，α肾上腺素能受体和Gq/磷脂酶C/PKC途径的激活对瞬时心肌收缩力几乎没有急性影响，但可成为心脏肥大的有力刺激因素。
通过在心脏特异性转基因中过表达各自信号通路的单个成分，已明确了α和β肾上腺素能途径在体内心脏中的不同作用，而使用传统药理学技术很难区分这些作用。α肾上腺素能受体或Gq异源三聚体G蛋白的α亚基过表达导致的心室重构表现为向心性或离心性肥大，无心室扩张或心肌纤维化。心肌细胞大小增加，一组与肥大相关的胚胎心脏基因重新表达。这些表型特征是压力超负荷肥大的特征，事实上，抑制Gq信号传导可预防小鼠压力超负荷肥大。通过Gq的信号传导增加超过导致肥大的水平会导致心肌细胞凋亡，并使代偿性肥大发展为扩张型心肌病。
β肾上腺素能受体或Gs异源三聚体G蛋白的α亚基的转基因过表达导致心肌收缩力如预期增加，但也会导致心肌细胞逐渐丧失，进而导致迟发性纤维化心肌病，从而重现了嗜铬细胞瘤或医源性儿茶酚胺输注时所见的儿茶酚胺心肌病临床综合征。β肾上腺素能受体的这些作用具有浓度依赖性，并且β1亚型似乎比β2亚型严重得多，这可能是因为β2与抑制性Gi偶联。
