Department of Clinical Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg, Kiel, Lübeck, Germany.
Department of Clinical Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
J Mol Cell Cardiol. 2019 Feb;127:31-43. doi: 10.1016/j.yjmcc.2018.12.001. Epub 2018 Dec 4.
The sympathetic nervous system is the main stimulator of cardiac function. While acute activation of the β-adrenoceptors exerts positive inotropic and lusitropic effects by increasing cAMP and Ca, chronically enhanced sympathetic tone with changed β-adrenergic signaling leads to alterations of gene expression and remodeling. The CREB-regulated transcription coactivator 1 (CRTC1) is activated by cAMP and Ca. In the present study, the regulation of CRTC1 in cardiomyocytes and its effect on cardiac function and growth was investigated. In cardiomyocytes, isoprenaline induced dephosphorylation, and thus activation of CRTC1, which was prevented by propranolol. Crtc1-deficient mice exhibited left ventricular dysfunction, hypertrophy and enlarged cardiomyocytes. However, isoprenaline-induced contractility of isolated trabeculae or phosphorylation of cardiac troponin I, cardiac myosin-binding protein C, phospholamban, and ryanodine receptor were not altered, suggesting that cardiac dysfunction was due to the global lack of Crtc1. The mRNA and protein levels of the Gα GTPase activating protein regulator of G-protein signaling 2 (RGS2) were lower in hearts of Crtc1-deficient mice. Chromatin immunoprecipitation and reporter gene assays showed stimulation of the Rgs2 promoter by CRTC1. In Crtc1-deficient cardiomyocytes, phosphorylation of the Gα-downstream kinase ERK was enhanced. CRTC1 content was higher in cardiac tissue from patients with aortic stenosis or hypertrophic cardiomyopathy and from two murine models mimicking these diseases. These data suggest that increased CRTC1 in maladaptive hypertrophy presents a compensatory mechanism to delay disease progression in part by enhancing Rgs2 gene transcription. Furthermore, the present study demonstrates an important role of CRTC1 in the regulation of cardiac function and growth.
交感神经系统是心脏功能的主要刺激物。虽然β肾上腺素受体的急性激活通过增加 cAMP 和 Ca 发挥正性变力和变时作用，但长期增强的交感神经张力和改变的β肾上腺素能信号导致基因表达和重塑的改变。环磷腺苷反应元件结合蛋白 1（CRTC1）被 cAMP 和 Ca 激活。本研究旨在研究心肌细胞中 CRTC1 的调节及其对心脏功能和生长的影响。在心肌细胞中，异丙肾上腺素诱导 CRTC1 去磷酸化，从而激活，该过程被普萘洛尔所阻止。Crtc1 缺陷小鼠表现出左心室功能障碍、肥大和增大的心肌细胞。然而，异丙肾上腺素诱导的分离小梁的收缩性或心肌肌钙蛋白 I、心肌肌球蛋白结合蛋白 C、磷酸化酶和兰尼碱受体的磷酸化没有改变，这表明心脏功能障碍是由于全局缺乏 Crtc1 所致。Crtc1 缺陷小鼠心脏中的 Gα G 蛋白激活蛋白调节物 G 蛋白信号转导 2（RGS2）的 mRNA 和蛋白水平较低。染色质免疫沉淀和报告基因分析显示 CRTC1 刺激 Rgs2 启动子。在 Crtc1 缺陷的心肌细胞中，Gα 下游激酶 ERK 的磷酸化增强。CRTC1 在主动脉瓣狭窄或肥厚型心肌病患者的心脏组织中和模拟这些疾病的两种小鼠模型中的心脏组织中的含量较高。这些数据表明，适应性肥大中 CRTC1 的增加代表了一种代偿机制，通过增强 Rgs2 基因转录来部分延迟疾病进展。此外，本研究表明 CRTC1 在调节心脏功能和生长中具有重要作用。
