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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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(A) Appearance of 6-month-old transgenic (TG) mice homozygous for the ST3Gal-II transgene. Daily body weights gains (B, C) in TG and WT mice. (D) Kaplan–Meier survival plot for male and female TG mice. All hemizygous transgenic and WT mice survived until at least 1 year old (not plotted). (E) Body weights, heart weights, and heart:body weight ratios of TG (black bars) and WT (white bars) mice at 4 weeks of age (mean + SD; n = 3). (F) Biochemical analysis of mouse plasma enzymes (mean + SD; n = 5). Four enzyme activities were compared in plasma samples from TG (black bars) and WT (white bars) mice at 4 weeks of age. All plasma enzymes tested showed significantly higher activities in TG mice than in WT mice, even at a young age, long before the onset of symptoms. Asterisks in E and F indicate significant difference between WT and TG mice (n = 3; p < 0.05).
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fig02: (A) Appearance of 6-month-old transgenic (TG) mice homozygous for the ST3Gal-II transgene. Daily body weights gains (B, C) in TG and WT mice. (D) Kaplan–Meier survival plot for male and female TG mice. All hemizygous transgenic and WT mice survived until at least 1 year old (not plotted). (E) Body weights, heart weights, and heart:body weight ratios of TG (black bars) and WT (white bars) mice at 4 weeks of age (mean + SD; n = 3). (F) Biochemical analysis of mouse plasma enzymes (mean + SD; n = 5). Four enzyme activities were compared in plasma samples from TG (black bars) and WT (white bars) mice at 4 weeks of age. All plasma enzymes tested showed significantly higher activities in TG mice than in WT mice, even at a young age, long before the onset of symptoms. Asterisks in E and F indicate significant difference between WT and TG mice (n = 3; p < 0.05).

Mentions: Expressions of ST3Gal-II mRNA (Fig. 1C) were analyzed statistically among three genotypes using analysis of variance, followed by pairwise comparisons by the Tukey–Kramer method. Expressions of SGCD mRNA (Fig. 1F) and proteins (Figs. 1D, 1G, 6C, and 6D), the heart and body weight parameters (Fig. 2E), and biochemical analyses (Fig. 2F) were analyzed statistically between TG and WT mice using Student’s t-test. Differences with a p < 0.05 were considered statistically significant. All statistical analyses were conducted using StatView Version 5 (SAS Institute Inc., Cary, NC, U.S.A.).


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)

(A) Appearance of 6-month-old transgenic (TG) mice homozygous for the ST3Gal-II transgene. Daily body weights gains (B, C) in TG and WT mice. (D) Kaplan–Meier survival plot for male and female TG mice. All hemizygous transgenic and WT mice survived until at least 1 year old (not plotted). (E) Body weights, heart weights, and heart:body weight ratios of TG (black bars) and WT (white bars) mice at 4 weeks of age (mean + SD; n = 3). (F) Biochemical analysis of mouse plasma enzymes (mean + SD; n = 5). Four enzyme activities were compared in plasma samples from TG (black bars) and WT (white bars) mice at 4 weeks of age. All plasma enzymes tested showed significantly higher activities in TG mice than in WT mice, even at a young age, long before the onset of symptoms. Asterisks in E and F indicate significant difference between WT and TG mice (n = 3; p < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: (A) Appearance of 6-month-old transgenic (TG) mice homozygous for the ST3Gal-II transgene. Daily body weights gains (B, C) in TG and WT mice. (D) Kaplan–Meier survival plot for male and female TG mice. All hemizygous transgenic and WT mice survived until at least 1 year old (not plotted). (E) Body weights, heart weights, and heart:body weight ratios of TG (black bars) and WT (white bars) mice at 4 weeks of age (mean + SD; n = 3). (F) Biochemical analysis of mouse plasma enzymes (mean + SD; n = 5). Four enzyme activities were compared in plasma samples from TG (black bars) and WT (white bars) mice at 4 weeks of age. All plasma enzymes tested showed significantly higher activities in TG mice than in WT mice, even at a young age, long before the onset of symptoms. Asterisks in E and F indicate significant difference between WT and TG mice (n = 3; p < 0.05).
Mentions: Expressions of ST3Gal-II mRNA (Fig. 1C) were analyzed statistically among three genotypes using analysis of variance, followed by pairwise comparisons by the Tukey–Kramer method. Expressions of SGCD mRNA (Fig. 1F) and proteins (Figs. 1D, 1G, 6C, and 6D), the heart and body weight parameters (Fig. 2E), and biochemical analyses (Fig. 2F) were analyzed statistically between TG and WT mice using Student’s t-test. Differences with a p < 0.05 were considered statistically significant. All statistical analyses were conducted using StatView Version 5 (SAS Institute Inc., Cary, NC, U.S.A.).

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