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The effect of Sulfonulyrea short form (SUR2A-55) overexpression on cardiac gene expression

ABSTRACT: The small splice variant of the sulfonylurea receptor protein isoform 2A (SUR2A-55) targets mitochondria and enhances mitoKATP activity. In male mice the overexpression of this protein promotes cardioprotection protecting hearts from ischemia reperfusion injury. However, it is unclear what impact this has on the female myocardium as SUR2A and KATP channels are known to be differentially expressed in male and female hearts. To define the impact of SU2R2A-55 on the female heart, RNA seq was performed on hearts from mice with cardiac specific transgenic overexpression of SUR2A-55 (TGSUR2A-55). RNA seq analysis found 227 differnetial expressed genes between WT and TGSUR2A-55 female mouse hearts that were enriched in pathways of cellular metabolism. This was in direct contrast to male mice that had only three differentially expressed genes. Future research directed at the expression and activity of mitoKATP subunits according to sex may elucidate gender specific treatments.

ORGANISM(S): Mus musculus

PROVIDER: GSE245038 | GEO | 2023/10/16

REPOSITORIES: GEO

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Project description:Analysis of the effects of aging on the development of dilated cardiomyopathy by characterizing both changes in ejection fraction (EF) and gene expression profile in 3 groups of male mice: Control (Cont or WT, n=11) and transgenic (Tg or KO) mice with either high EF (KO-H or Tg-H, n=7) or low EF (KO-L or Tg-L, n=6). We previously produced a line of transgenic mice (Tg) on a mixed genetic background where cardiac-specific overexpression of Cre recombinase reduced expression of the EP4 receptor gene. There were no obvious phenotypes in 10-12-week-old male Tg mice. To determine if a cardiac phenotype developed in aged mice, we assessed cardiac structure and function by echocardiography, histology and gene expression in 23-33-week-old male Tg and littermates (Cont). After echocardiography, hearts were removed to assess hypertrophy (MCSA), fibrosis (ICF) and macrophage infiltration by histological methods and for extraction of total RNA and protein. Cont mice had a normal EF of 80Â±0.6% (n=70), whereas Tg mice had a lower EF (60Â±2.7%, n=55, p<0.001) coupled with left ventricular dilatation. The distribution of EFs in the Tg mice was large, ranging from normal to below 30%. MCSA and infiltrating macrophages were not different between groups, but ICF increased by 35% in Tg mice. Cre protein levels in heart lysates did not correlate with either age or EF. In contrast to male Tg mice, female Tg mice had no cardiac dysfunction assessed by echocardiography from 12 to 28 weeks of age. To understand gene expression differences between Cont and Tg mice, whole genome gene expression profiling (Illumina BeadChips) on hearts of 30-32 week old male mice was done. Data indicated that 595 genes were overexpressed in the Tg hearts, 156 of which changed more than 2-fold, including genes involved in remodeling, inflammation, and oxidative stress. 512 genes were downregulated in the Cont hearts, 79 of which changed more than 2-fold, including genes involved with calcium handling, K+ channels, and fatty acid transport and metabolism. In conclusion, Cre overexpression and EP4 knock down in cardiac myocytes in aged male but not female Tg mice are in part associated with increased fibrosis, reduced EF and dilated cardiomyopathy; however, Cre protein itself does not seem to be responsible for the cardiomyopathy. The absence of cardiac dysfunction in female mice suggests a sexual dimorphism in the phenotype. Creation of the cardiac-myocyte specific EP4 KO mouse and littermate controls was described in JY Qian et al, Hypertension 2008: 51(pt 2):560-566. Total RNA extracted from left ventricle of control (Cont or WT, n =11) and cardiac-specific EP4 KO (Tg or KO, n=13) male mice (mean age 31 weeks).

Project description:Analysis of the effects of aging on the development of dilated cardiomyopathy by characterizing both changes in ejection fraction (EF) and gene expression profile in 3 groups of male mice: Control (Cont or WT, n=11) and transgenic (Tg or KO) mice with either high EF (KO-H or Tg-H, n=7) or low EF (KO-L or Tg-L, n=6). We previously produced a line of transgenic mice (Tg) on a mixed genetic background where cardiac-specific overexpression of Cre recombinase reduced expression of the EP4 receptor gene. There were no obvious phenotypes in 10-12-week-old male Tg mice. To determine if a cardiac phenotype developed in aged mice, we assessed cardiac structure and function by echocardiography, histology and gene expression in 23-33-week-old male Tg and littermates (Cont). After echocardiography, hearts were removed to assess hypertrophy (MCSA), fibrosis (ICF) and macrophage infiltration by histological methods and for extraction of total RNA and protein. Cont mice had a normal EF of 80±0.6% (n=70), whereas Tg mice had a lower EF (60±2.7%, n=55, p<0.001) coupled with left ventricular dilatation. The distribution of EFs in the Tg mice was large, ranging from normal to below 30%. MCSA and infiltrating macrophages were not different between groups, but ICF increased by 35% in Tg mice. Cre protein levels in heart lysates did not correlate with either age or EF. In contrast to male Tg mice, female Tg mice had no cardiac dysfunction assessed by echocardiography from 12 to 28 weeks of age. To understand gene expression differences between Cont and Tg mice, whole genome gene expression profiling (Illumina BeadChips) on hearts of 30-32 week old male mice was done. Data indicated that 595 genes were overexpressed in the Tg hearts, 156 of which changed more than 2-fold, including genes involved in remodeling, inflammation, and oxidative stress. 512 genes were downregulated in the Cont hearts, 79 of which changed more than 2-fold, including genes involved with calcium handling, K+ channels, and fatty acid transport and metabolism. In conclusion, Cre overexpression and EP4 knock down in cardiac myocytes in aged male but not female Tg mice are in part associated with increased fibrosis, reduced EF and dilated cardiomyopathy; however, Cre protein itself does not seem to be responsible for the cardiomyopathy. The absence of cardiac dysfunction in female mice suggests a sexual dimorphism in the phenotype. Creation of the cardiac-myocyte specific EP4 KO mouse and littermate controls was described in JY Qian et al, Hypertension 2008: 51(pt 2):560-566.

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The effect of Sulfonulyrea short form (SUR2A-55) overexpression on cardiac gene expression

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