Department of Internal Medicine-Cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Alcohol Clin Exp Res. 2010 Jul;34(7):1171-81. doi: 10.1111/j.1530-0277.2010.01194.x. Epub 2010 May 12.
Recent studies link altered cardiac beta-adrenergic receptor (AR) signaling to the pathology of alcoholic cardiomyopathy (ACM). However, the alteration and functional effect of beta(3)-AR activation in ACM are unknown. We tested the hypothesis that chronic alcohol intake causes an up-regulation of cardiac beta(3)-AR, which exacerbates myocyte dysfunction and impairs calcium regulation, thereby directly contributing to the progression of ACM.
We compared myocyte beta(3)- and beta(1)-AR expression and myocyte contractile (Ca(2+)), transient (Ca(2+)), and Ca(2+) current (I(Ca,L)) responses to beta- and beta(3)-AR stimulation in myocytes obtained from left ventricle (LV) tissue samples obtained from 10 normal control (C) and 16 monkeys with self-administered alcohol for 12 months prior to necropsy: 6 moderate (M) and 10 heavy (H) drinkers with group average alcohol intakes of 1.5 +/- 0.2 and 3.3 +/- 0.2 g/kg/d, respectively.
Compared with control myocytes (C), in alcoholic cardiomyocytes, basal cell contraction (dL/dt(max), -39%, H: 69.8 vs. C: 114.6 microm/s), relaxation (dR/dt(max), -37%, 58.2 vs. 92.9 microm/s), Ca(2+) (-34%, 0.23 vs. 0.35), and I(Ca,L) (-25%, 4.8 vs. 6.4pA/pF) were all significantly reduced. Compared with controls, in moderate and heavy drinkers, beta(1)-AR protein levels decreased by 23% and 42%, but beta(3)-AR protein increased by 46% and 85%, respectively. These changes were associated with altered myocyte functional responses to beta-AR agonist, isoproterenol (ISO), and beta(3)-AR agonist, BRL-37344 (BRL). Compared with controls, in alcoholic myocytes, ISO (10(-8) M) produced significantly smaller increases in dL/dt(max) (H: 40% vs. C: 71%), dR/dt(max) (37% vs. 52%), Ca(2+) (17% vs. 37%), and I(Ca,L) (17% vs. 27%), but BRL (10(-8) M) produced a significantly greater decrease in dL/dt(max) (H: -23% vs. C: -11%), Ca(2+) (-30% vs. -11%), and I(Ca,L) (-28% vs. -17%).
Chronic alcohol consumption down-regulates cardiac beta(1)- and up-regulates beta(3)-ARs, contributing to the abnormal response to catecholamines in ACM. The up-regulation of cardiac beta(3)-AR signaling enhances inhibition of LV myocyte contraction and relaxation and exacerbates the dysfunctional Ca(2+) regulation and, thus, may precede the development of ACM.
最近的研究表明，心脏β-肾上腺素能受体（AR）信号的改变与酒精性心肌病（ACM）的病理学有关。然而，β（3）-AR 激活的改变及其功能效应在 ACM 中尚不清楚。我们检验了这样一个假设，即长期饮酒会导致心脏β（3）-AR 的上调，从而加剧心肌细胞功能障碍和钙调节受损，从而直接导致 ACM 的进展。
我们比较了心肌细胞β（3）-和β（1）-AR 的表达，以及心肌细胞收缩（[Ca（2+）]（i））、短暂（[Ca（2+）]（iT））和 Ca（2+）电流（I（Ca，L））对β-和β（3）-AR 刺激的反应，这些刺激来自左心室（LV）组织样本，这些样本来自 10 名正常对照（C）和 16 名猴子，这些猴子在尸检前 12 个月自行饮酒：6 名中度（M）和 10 名重度（H）饮酒者，组平均饮酒量分别为 1.5 +/- 0.2 和 3.3 +/- 0.2 g/kg/d。
与对照心肌细胞（C）相比，在酒精性心肌病细胞中，基础细胞收缩（dL/dt（max），-39%，H：69.8 vs. C：114.6 μm/s）、舒张（dR/dt（max），-37%，58.2 vs. C：92.9 μm/s）、[Ca（2+）]（iT）（-34%，0.23 vs. 0.35）和 I（Ca，L）（-25%，4.8 vs. 6.4 pA/pF）均显著降低。与对照组相比，在中度和重度饮酒者中，β（1）-AR 蛋白水平分别下降 23%和 42%，但β（3）-AR 蛋白分别增加 46%和 85%。这些变化与心肌细胞对β-AR 激动剂异丙肾上腺素（ISO）和β（3）-AR 激动剂 BRL-37344（BRL）的功能反应改变有关。与对照组相比，在酒精性心肌细胞中，ISO（10（-8）M）对 dL/dt（max）的增加明显较小（H：40% vs. C：71%），dR/dt（max）（37% vs. 52%），[Ca（2+）]（iT）（17% vs. 37%）和 I（Ca，L）（17% vs. 27%），但 BRL（10（-8）M）对 dL/dt（max）的降低更为明显（H：-23% vs. C：-11%），[Ca（2+）]（iT）（-30% vs. -11%）和 I（Ca，L）（-28% vs. -17%）。
慢性酒精摄入下调心脏β（1）-并上调β（3）-AR，导致 ACM 对儿茶酚胺的异常反应。心脏β（3）-AR 信号的上调增强了对 LV 心肌细胞收缩和舒张的抑制作用，并加剧了功能障碍的[Ca（2+）]调节，因此可能先于 ACM 的发展。
