Upregulation of functional β3-adrenergic receptor in the failing canine myocardium
Upregulation of functional β3-adrenergic receptor in the failing canine myocardium
复制标题
DOI：
10.1161/hh1901.098042
复制
发表时间：
2001-09-28
影响因子：
20.1
通讯作者：
Cheng, CP
中科院分区：
文献类型：
--
作者：
Cheng, HJ;Zhang, ZS;Cheng, CP
对心脏β 3肾上腺素能受体（AR）的表达和功能反应的改变可能导致心力衰竭（CHF）中的进行性心功能障碍。我们比较了9只装有仪器的狗在起搏诱导的CHF之前和之后对BRL-37344（BRL，10（-8）mol/L）（一种选择性β（3）-AR激动剂）的肌细胞β（3）-AR mRNA和蛋白水平以及肌细胞收缩、[Ca 2 +]（i）瞬时和Ca 2+电流（I-Ca.L）反应。从左心室心肌活检组织中分离肌细胞。采用逆转录-聚合酶链反应（RT-PCR）技术，从每只动物心肌细胞总RNA中检测β（3）-AR mRNA。用克隆的犬β（3）-AR cDNA探针和心肌细胞poly A（+）RNA，我们在正常和CHF心肌细胞中检测到约3.4kb的单一条带。Western blot检测β（3）-AR蛋白表达。β（3）-AR mRNA和蛋白水平在CHF心肌细胞中显著高于正常心肌细胞。重要的是，这些变化与增强的β（3）-AR介导的对肌细胞收缩反应和[Ca 2 +]（i）调节的负性调节有关。与正常心肌细胞相比，CHF心肌细胞在BRL时缩短和再延长速度明显降低，同时伴有收缩期[Ca 2 +]（i）瞬时峰值和I-Ca. L的明显降低。用美托洛尔（一种β（1）-AR拮抗剂）或纳多洛尔（一种β（1）-和β（2）-AR拮抗剂）预处理心肌细胞并不能改变这些反应，但布萘洛尔或L-748，337（β（3）-AR拮抗剂）几乎可以阻止这些反应。我们的结论是，在起搏诱导的CHF犬中，β（3）-AR基因表达和蛋白水平上调，对β（3）-AR刺激的功能反应增加。这可能有助于CHF中心功能不全的进展。
Altered expression and functional responses to cardiac beta (3)-adrenergic receptors (ARs) may contribute to progressive cardiac dysfunction in heart failure (CHF). We compared myocyte beta (3)-AR mRNA and protein levels and myocyte contractile, [Ca2+](i) transient, and Ca2+ current (I-Ca.L) responses to BRL-37344 (BRL, 10(-8) mol/L), a selective beta (3)-AR agonist, in 9 instrumented dogs before and after pacing-induced CHF. Myocytes were isolated from left ventricular myocardium biopsy tissues. Using reverse transcription-polymerase chain reaction, we detected beta (3)-AR mRNA from myocyte total RNA in each animal. Using a cloned canine beta (3)-AR cDNA probe and myocyte poly A(+) RNA, we detected a single band about 3.4 kb in normal and CHF myocytes. beta (3)-AR protein was detected by Western blot. beta (3)-AR mRNA and protein levels were significantly greater in CHF myocytes than in normal myocytes. Importantly, these changes were associated with enhanced beta (3)-AR-mediated negative modulation on myocyte contractile response and [Ca2+](i) regulation. Compared with normal myocytes, CHF myocytes had much greater decreases in the velocity of shortening and relengthening with BRL accompanied by larger reductions in the peak systolic [Ca2+](i) transient and I-Ca.L. These responses were not modified by pretreating myocytes with metoprolol (a beta (1)-AR antagonist) or nadolol (a beta (1)- and beta (2)-AR antagonist), but were nearly prevented by bupranolol or L-748,337 (beta (3)-AR antagonists). We conclude that in dogs with pacing-induced CHF, beta (3)-AR gene expression and protein levels are upregulated, and the functional response to beta (3)-AR stimulation is increased. This may contribute to progression of cardiac dysfunction in CHF.