Deng Wei, Ednie Andrew R, Qi Jianyong, Bennett Eric S
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, MDC 8, 12901 Bruce B. Downs Blvd., Tampa, FL, 33612-4799, USA.
Intensive Care Laboratory, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, People's Republic of China.
Basic Res Cardiol. 2016 Sep;111(5):57. doi: 10.1007/s00395-016-0574-1. Epub 2016 Aug 9.
Dilated cardiomyopathy (DCM), the third most common cause of heart failure, is often associated with arrhythmias and sudden cardiac death if not controlled. The majority of DCM is of unknown etiology. Protein sialylation is altered in human DCM, with responsible mechanisms not yet described. Here we sought to investigate the impact of clinically relevant changes in sialylation on cardiac function using a novel model for altered glycoprotein sialylation that leads to DCM and to chronic stress-induced heart failure (HF), deletion of the sialyltransferase, ST3Gal4. We previously reported that 12- to 20-week-old ST3Gal4 (-/-) mice showed aberrant cardiac voltage-gated ion channel sialylation and gating that contribute to a pro-arrhythmogenic phenotype. Here, echocardiography supported by histology revealed modest dilated and thinner-walled left ventricles without increased fibrosis in ST3Gal4 (-/-) mice starting at 1 year of age. Cardiac calcineurin expression in younger (16-20 weeks old) ST3Gal4 (-/-) hearts was significantly reduced compared to WT. Transverse aortic constriction (TAC) was used as a chronic stressor on the younger mice to determine whether the ability to compensate against a pathologic insult is compromised in the ST3Gal4 (-/-) heart, as suggested by previous reports describing the functional implications of reduced cardiac calcineurin levels. TAC'd ST3Gal4 (-/-) mice presented with significantly reduced systolic function and ventricular dilation that deteriorated into congestive HF within 6 weeks post-surgery, while constricted WT hearts remained well-adapted throughout (ejection fraction, ST3Gal4 (-/-) = 34 ± 5.2 %; WT = 53.8 ± 7.4 %; p < 0.05). Thus, a novel, sialo-dependent model for DCM/HF is described in which clinically relevant reduced sialylation results in increased arrhythmogenicity and reduced cardiac calcineurin levels that precede cardiomyopathy and TAC-induced HF, suggesting a causal link among aberrant sialylation, chronic arrhythmia, reduced calcineurin levels, DCM in the absence of a pathologic stimulus, and stress-induced HF.
扩张型心肌病（DCM）是心力衰竭的第三大常见病因，若不加以控制，常与心律失常和心源性猝死相关。大多数DCM病因不明。人类DCM中蛋白质唾液酸化发生改变，但其相关机制尚未阐明。在此，我们试图利用一种新型糖蛋白唾液酸化改变模型来研究临床上相关的唾液酸化变化对心脏功能的影响，该模型会导致DCM和慢性应激诱导的心力衰竭（HF），即唾液酸转移酶ST3Gal4的缺失。我们之前报道，12至20周龄的ST3Gal4（-/-）小鼠表现出异常的心脏电压门控离子通道唾液酸化和门控，这促成了致心律失常表型。在此，组织学支持下的超声心动图显示，1岁起的ST3Gal4（-/-）小鼠左心室有适度扩张且壁变薄，但纤维化未增加。与野生型相比，年轻（16至20周龄）的ST3Gal4（-/-）心脏中钙调神经磷酸酶表达显著降低。横向主动脉缩窄（TAC）被用作年轻小鼠的慢性应激源，以确定如先前报道中所述的心脏钙调神经磷酸酶水平降低的功能影响所表明的那样，ST3Gal4（-/-）心脏对抗病理性损伤的代偿能力是否受损。接受TAC处理的ST3Gal4（-/-）小鼠出现收缩功能显著降低和心室扩张，在手术后6周内恶化为充血性HF，而缩窄的野生型心脏在整个过程中仍保持良好适应（射血分数，ST3Gal4（-/-） = 34 ± 5.2%；野生型 = 53.8 ± 7.4%；p < 0.05）。因此，我们描述了一种新型的、依赖唾液酸的DCM/HF模型，其中临床上相关的唾液酸化减少导致致心律失常性增加和心脏钙调神经磷酸酶水平降低，这先于心肌病和TAC诱导的HF，提示异常唾液酸化、慢性心律失常、钙调神经磷酸酶水平降低、无病理性刺激时的DCM以及应激诱导的HF之间存在因果联系。
