The contributions of cardiac myosin binding protein C and troponin I phosphorylation to -adrenergic enhancement of in vivo cardiac function
The contributions of cardiac myosin binding protein C and troponin I phosphorylation to -adrenergic enhancement of in vivo cardiac function
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DOI：
10.1113/jp270959
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发表时间：
2016-02-01
影响因子：
5.5
通讯作者：
Stelzer, Julian E.
中科院分区：
文献类型：
--
作者：
Gresham, Kenneth S.;Stelzer, Julian E.
肾上腺素能刺激在加速心室收缩和加速舒张以使心输出量与不断变化的循环需求相匹配方面起着关键作用。两种关键的肌丝蛋白，肌钙蛋白I （TnI）和肌球蛋白结合蛋白c (MyBP-C)，在β -肾上腺素能刺激后被磷酸化；然而，它们对增强体内心脏收缩力的相对贡献尚不清楚。为了研究TnI和MyBP-C磷酸化在β -肾上腺素能介导的心功能增强中的作用，将表达非磷酸化TnI蛋白激酶A （PKA）残基（即丝氨酸在Ser23/24处取代丙氨酸；TnI(PKA-)）的转基因（TG）小鼠与表达非磷酸化MyBP-C PKA残基（即丝氨酸在Ser273、Ser282和Ser302处取代丙氨酸）的小鼠杂交；MyBPC(PKA-))产生一种新的小鼠模型，表达TnI和MyBP-C （DBLPKA-）中不可磷酸化的PKA残基。MyBP-C去磷酸化导致MyBPC（PKA-）和DBLPKA-小鼠心脏肥大和壁厚增加，体内超声心动图和压力-容量导管研究显示，与野生型和TnI（PKA-）小鼠相比，收缩功能受损和舒张舒张时间延长。输注β激动剂多巴酚丁胺导致所有小鼠的压力发展和放松速度加快；然而，与野生型和TnI（PKA-）小鼠相比，MyBPC（PKA-）和DBLPKA-小鼠表现出迟钝的收缩反应。此外，未麻醉的MyBPC（PKA-）和DBLPKA-小鼠使用植入式遥测装置测量多巴酚丁胺后最大收缩压降低。综上所述，我们的数据表明MyBP-C磷酸化是体内β -肾上腺素能刺激增强导致的压力发展和松弛加速的关键调节剂，MyBP-C磷酸化的降低可能是心力衰竭中肾上腺素能储备下降的基础。
beta-adrenergic stimulation plays a critical role in accelerating ventricular contraction and speeding relaxation to match cardiac output to changing circulatory demands. Two key myofilaments proteins, troponin I (TnI) and myosin binding protein-C (MyBP-C), are phosphorylated following beta-adrenergic stimulation; however, their relative contributions to the enhancement of in vivo cardiac contractility are unknown. To examine the roles of TnI and MyBP-C phosphorylation in beta-adrenergic-mediated enhancement of cardiac function, transgenic (TG) mice expressing non-phosphorylatable TnI protein kinase A (PKA) residues (i.e. serine to alanine substitution at Ser23/24; TnI(PKA-)) were bred with mice expressing non-phosphorylatable MyBP-C PKA residues (i.e. serine to alanine substitution at Ser273, Ser282 and Ser302; MyBPC(PKA-)) to generate a novel mouse model expressing non-phosphorylatable PKA residues in TnI and MyBP-C (DBLPKA-). MyBP-C dephosphorylation produced cardiac hypertrophy and increased wall thickness in MyBPC(PKA-) and DBLPKA- mice, and in vivo echocardiography and pressure-volume catheterization studies revealed impaired systolic function and prolonged diastolic relaxation compared to wild-type and TnI(PKA-) mice. Infusion of the beta-agonist dobutamine resulted in accelerated rates of pressure development and relaxation in all mice; however, MyBPC(PKA-) and DBLPKA- mice displayed a blunted contractile response compared to wild-type and TnI(PKA-) mice. Furthermore, unanaesthesized MyBPC(PKA-) and DBLPKA- mice displayed depressed maximum systolic pressure in response to dobutamine as measured using implantable telemetry devices. Taken together, our data show that MyBP-C phosphorylation is a critical modulator of the invivo acceleration of pressure development and relaxation as a result of enhanced beta-adrenergic stimulation, and reduced MyBP-C phosphorylation may underlie depressed adrenergic reserve in heart failure.