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Aberrant sialylation causes dilated cardiomyopathy and stress-induced heart failure

Abstract

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.

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Acknowledgments

We would like to thank Dr. Jamey Marth for generously providing the ST3Gal4 +/ mouse strain. This work was supported, in part, by two Grants from the National Science Foundation [IOS-1146882 and CMMI-1266331]; an American Heart Association, Greater Southeast Affiliate Grant-In-Aid [14GRNT20450148]; an American Heart Association, Greater Southeast Affiliate Postdoctoral Fellowship [15POST25710010]; and a Grant from the National Heart, Lung, Blood Institute [1R01HL102171-03].

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Correspondence to Eric S. Bennett.

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All animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Specific national laws have been observed. The manuscript does not contain clinical studies or patient data.

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Deng, W., Ednie, A.R., Qi, J. et al. Aberrant sialylation causes dilated cardiomyopathy and stress-induced heart failure. Basic Res Cardiol 111, 57 (2016). https://doi.org/10.1007/s00395-016-0574-1

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  • DOI: https://doi.org/10.1007/s00395-016-0574-1

Keywords

  • Dilated cardiomyopathy
  • Sialic acid
  • Echocardiography
  • Congenital disorders of glycosylation
  • Arrhythmic heart failure
  • Animal models
  • Calcineurin