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Cardiomyocyte sialylation and complex N‐glycosylation protect against dilated cardiomyopathy and heart failure (697.2)
Author(s) -
Deng Wei,
Ednie Andrew,
Bennett Eric
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.697.2
Subject(s) - dilated cardiomyopathy , heart failure , cardiomyopathy , medicine , ventricle , glycoprotein , ejection fraction , glycosylation , endocrinology , cardiac function curve , major histocompatibility complex , biology , chemistry , microbiology and biotechnology , immunology , antigen , biochemistry
Human congenital disorders of glycosylation are characterized by variably reduced glycoprotein glycosylation resulting in multi‐system effects, including cardiac dysfunction. We seek to understand whether and how reduced glycosylation contributes to cardiac symptoms and reported previously that the reduced glycoprotein sialylation that results from the global gene deletion of a cardiac expressing sialyltransferase, ST3Gal4, contributed to pressure‐induced heart failure (FASEB J, 2013, 27:595.2). Here we questioned whether cardiomyocyte‐specific (αMHC‐Cre) deletion of mannosyl (alpha‐1,3‐)‐glycoprotein beta‐1,2‐N‐acetylglucosaminyltransferase, Mgat1, responsible for initiating synthesis of complex and hybrid N‐glycans, contributes to the onset of dilated cardiomyopathy. At age 16 weeks (earliest time point tested), homozygous floxed Mgat1 and αMHC‐Cre positive mice, Mgat1 F/F αMHC‐Cre, showed significantly reduced ejection fraction (EF) and fractional shortening (FS) compared to littermate controls (in %, for controls (n=8), EF = 73.8 ± 2.1, FS = 42.5 ± 1.8; for Mgat1 F/F αMHC‐Cre mice (n=7), EF = 61.4 ± 2.3; FS = 32.8 ± 1.6; p<0.002). Systolic function of Mgat1 F/F αMHC‐Cre mice, but not of control mice, continued to deteriorate with age (at 30 weeks, Mgat1 F/F αMHC‐Cre mice (n=5) in %: EF = 38.2 ± 4.5; FS = 18.8 ± 2.5; p<0.0005). Mgat1 F/F αMHC‐Cre mice presented with apparent dilated cardiomyopathy indicated by reduced systolic function, a thinner wall and larger internal diameter of the left ventricle (p<0.0005) with no apparent increase in left ventricular mass index, and marked right and left ventricular dilatation observed during necropsy. Together, our data suggest sialylation and complex N‐glycosylation are necessary for normal cardiac function, and reduced cardiomyocyte N‐glycosylation contributes to the onset of significant ventricular systolic dysfunction consistent with dilated cardiomyopathy leading to heart failure. Grant Funding Source : Supported by NSF grant # IOS‐1146882