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Adult onset cardiac dilatation in a transgenic mouse line with Galβ1,3GalNAc α2,3-sialyltransferase II (ST3Gal-II) transgenes: a new model for dilated cardiomyopathy.

Suzuki O, Kanai T, Nishikawa T, Yamamoto Y, Noguchi A, Takimoto K, Koura M, Noguchi Y, Uchio-Yamada K, Tsuji S, Matsuda J - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2011)

Bottom Line: Sugar chain abnormalities in glycolipids and glycoproteins are associated with various diseases.Although no apparent change was found in heart gangliosides, glycosylation of heart proteins was altered.Interestingly, sugar moieties not directly related to the ST3Gal-II catalytic reaction were also changed.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Ibaraki, Japan. osuzuki@nibio.go.jp

ABSTRACT
Sugar chain abnormalities in glycolipids and glycoproteins are associated with various diseases. Here, we report an adult onset cardiac dilatation in a transgenic mouse line with Galβ1,3GalNAc α2,3-sialyltransferase II (ST3Gal-II) transgenes. The transgenic hearts at the end-stage, at around 7 months old, were enlarged, with enlarged cavities and thin, low-tensile walls, typical of dilated cardiomyopathy. Although no apparent change was found in heart gangliosides, glycosylation of heart proteins was altered. Interestingly, sugar moieties not directly related to the ST3Gal-II catalytic reaction were also changed. Significant increases in calreticulin and calnexin were observed in hearts of the transgenic mice. These results suggest that expression of ST3Gal-II transgenes induces abnormal protein glycosylation, which disorganizes the endoplasmic/sarcoplasmic reticulum quality control system and elevates the calreticulin/calnexin level, resulting in suppression of cardiac function. The transgenic mice showed 100% incidence of adult onset cardiac dilatation, suggesting great potential as a new model for dilated cardiomyopathy.

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Related in: MedlinePlus

Frozen sections of heart (A) and rectus femoris muscle (B) treated with or without α2,3-sialidase and stained with biotinylated PNA lectin, followed by FITC-avidin D. Bars = 10 µm. PNA binding was localized to pericellular regions without sialidase treatment, whereas the reactivity was essentially the same between TG and WG hearts. The reactivity in TG muscle was higher than in WT muscle. After sialidase treatment, PNA binding in both became evident equally in TG and WT heart and muscle.
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fig07: Frozen sections of heart (A) and rectus femoris muscle (B) treated with or without α2,3-sialidase and stained with biotinylated PNA lectin, followed by FITC-avidin D. Bars = 10 µm. PNA binding was localized to pericellular regions without sialidase treatment, whereas the reactivity was essentially the same between TG and WG hearts. The reactivity in TG muscle was higher than in WT muscle. After sialidase treatment, PNA binding in both became evident equally in TG and WT heart and muscle.

Mentions: Sialylation in heart and skeletal muscle tissues with transgene-derived ST3Gal-II was examined by histochemical analysis using PNA lectin in combination with α2,3-sialidase treatment (Fig. 7). The ST3Gal-II enzyme converts sugars (Galβ1,3GalNAc) that are bound by PNA to sugars (SialGalβ1,3GalNAc) that are not bound by PNA by α2,3-sialylation of terminal galactose residues. The α2,3-sialidase enzyme reverses the reaction. In the heart, the staining was essentially the same between TG and WT mice with and without α2,3-sialidase treatment. In contrast, PNA staining in the TG skeletal muscle tissue was more intense than that in the WT tissue even without α2,3-sialidase treatment. Staining in skeletal muscle tissue was essentially the same between TG and WT mice after the α2,3-sialidase treatment. These results indicated that most of the terminal Galβ1,3GalNAc structures in pericellular regions (cell membranes and ECM) were sialylated via the α2,3 linkage of galactose residues in the heart. The sialylation decreased in skeletal muscle of TG mice compared with that in WT mice. After α2,3-sialidase treatment, the TG and WT tissues showed similar staining patterns, indicating that the differential staining by PNA without α2,3-sialidase treatment was attributable to differential α2,3-sialylation of Gal-GalNAc structures and not different amounts of Gal-GalNAc structures.


Adult onset cardiac dilatation in a transgenic mouse line with Galβ1,3GalNAc α2,3-sialyltransferase II (ST3Gal-II) transgenes: a new model for dilated cardiomyopathy.

Suzuki O, Kanai T, Nishikawa T, Yamamoto Y, Noguchi A, Takimoto K, Koura M, Noguchi Y, Uchio-Yamada K, Tsuji S, Matsuda J - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2011)

Frozen sections of heart (A) and rectus femoris muscle (B) treated with or without α2,3-sialidase and stained with biotinylated PNA lectin, followed by FITC-avidin D. Bars = 10 µm. PNA binding was localized to pericellular regions without sialidase treatment, whereas the reactivity was essentially the same between TG and WG hearts. The reactivity in TG muscle was higher than in WT muscle. After sialidase treatment, PNA binding in both became evident equally in TG and WT heart and muscle.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3313694&req=5

fig07: Frozen sections of heart (A) and rectus femoris muscle (B) treated with or without α2,3-sialidase and stained with biotinylated PNA lectin, followed by FITC-avidin D. Bars = 10 µm. PNA binding was localized to pericellular regions without sialidase treatment, whereas the reactivity was essentially the same between TG and WG hearts. The reactivity in TG muscle was higher than in WT muscle. After sialidase treatment, PNA binding in both became evident equally in TG and WT heart and muscle.
Mentions: Sialylation in heart and skeletal muscle tissues with transgene-derived ST3Gal-II was examined by histochemical analysis using PNA lectin in combination with α2,3-sialidase treatment (Fig. 7). The ST3Gal-II enzyme converts sugars (Galβ1,3GalNAc) that are bound by PNA to sugars (SialGalβ1,3GalNAc) that are not bound by PNA by α2,3-sialylation of terminal galactose residues. The α2,3-sialidase enzyme reverses the reaction. In the heart, the staining was essentially the same between TG and WT mice with and without α2,3-sialidase treatment. In contrast, PNA staining in the TG skeletal muscle tissue was more intense than that in the WT tissue even without α2,3-sialidase treatment. Staining in skeletal muscle tissue was essentially the same between TG and WT mice after the α2,3-sialidase treatment. These results indicated that most of the terminal Galβ1,3GalNAc structures in pericellular regions (cell membranes and ECM) were sialylated via the α2,3 linkage of galactose residues in the heart. The sialylation decreased in skeletal muscle of TG mice compared with that in WT mice. After α2,3-sialidase treatment, the TG and WT tissues showed similar staining patterns, indicating that the differential staining by PNA without α2,3-sialidase treatment was attributable to differential α2,3-sialylation of Gal-GalNAc structures and not different amounts of Gal-GalNAc structures.

Bottom Line: Sugar chain abnormalities in glycolipids and glycoproteins are associated with various diseases.Although no apparent change was found in heart gangliosides, glycosylation of heart proteins was altered.Interestingly, sugar moieties not directly related to the ST3Gal-II catalytic reaction were also changed.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Ibaraki, Japan. osuzuki@nibio.go.jp

ABSTRACT
Sugar chain abnormalities in glycolipids and glycoproteins are associated with various diseases. Here, we report an adult onset cardiac dilatation in a transgenic mouse line with Galβ1,3GalNAc α2,3-sialyltransferase II (ST3Gal-II) transgenes. The transgenic hearts at the end-stage, at around 7 months old, were enlarged, with enlarged cavities and thin, low-tensile walls, typical of dilated cardiomyopathy. Although no apparent change was found in heart gangliosides, glycosylation of heart proteins was altered. Interestingly, sugar moieties not directly related to the ST3Gal-II catalytic reaction were also changed. Significant increases in calreticulin and calnexin were observed in hearts of the transgenic mice. These results suggest that expression of ST3Gal-II transgenes induces abnormal protein glycosylation, which disorganizes the endoplasmic/sarcoplasmic reticulum quality control system and elevates the calreticulin/calnexin level, resulting in suppression of cardiac function. The transgenic mice showed 100% incidence of adult onset cardiac dilatation, suggesting great potential as a new model for dilated cardiomyopathy.

Show MeSH
Related in: MedlinePlus