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ERRalpha wt vs. ko hearts, baseline

ABSTRACT: We hypothesized that the estrogen-related receptor a (ERRa), which recruits PGC-1a to metabolic target genes in heart, exerts protective effects in the context of stressors known to cause heart failure. ERRa-/- mice subjected to left ventricular (LV) pressure overload developed signatures of heart failure including chamber dilatation and reduced LV fractional shortening. 31P-NMR studies revealed abnormal phosphocreatine depletion in ERRa-/- hearts subjected to hemodynamic stress, indicative of a defect in ATP reserve. Mitochondrial respiration studies demonstrated reduced maximal ATP synthesis rates in ERRa-/- hearts. Cardiac ERRa target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer were downregulated in ERRa-/- mice at baseline or with pressure overload. These results demonstrate that ERRa, a potential therapeutic target, is indispensable for the adaptive bioenergetic response to hemodynamic stressors known to cause heart failure. Keywords: Genetic modification, stress response

ORGANISM(S): Mus musculus

PROVIDER: GSE8106 | GEO | 2007/10/16

SECONDARY ACCESSION(S): PRJNA100969

REPOSITORIES: GEO

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Project description:Aims: Cardiomyocyte-specific nitric oxide synthase 3 (NOS3) overexpression reduces left ventricular (LV) remodelling after myocardial infarction in mice, but its effect on sustained LV pressure-overload remains incompletely understood. We investigated LV structural and functional adaptation to elevated afterload in mice with cardiomyocyte-restricted NOS3 overexpression (NOS3TG) and wild type littermates (WT). Methods and Results: Hemodynamic indices, cardiac hypertrophy and interstitial fibrosis were measured 10 weeks after transverse aortic constriction (TAC). After 10 weeks TAC, NOS3TG had better preserved systolic function (maximum rates of pressure development normalized to maximal pressure 77Â±6 versus 65Â±2 ms-1, P=0.05), reduced heart weight-body weight ratio (HW/BW, 5.0Â±0.3 versus 5.8Â±0.1, P<0.05), and cardiomyocyte width than WT (14.9Â±0.4 vs 16.7Â±0.2 ?m, P<0.05). After 10 weeks TAC, a 44k cDNA chip-based microarray analysis was validated using real time PCR and revealed significantly altered expression pattern of genes involved in cellular growth, matrix remodelling, and inflammation between genotypes. Conclusions: Cardiomyocyte-restricted NOS3 overexpression attenuates TAC-induced hypertrophy via autocrine inhibition of cardiomyocyte cell growth, but does not mitigate myocardial fibrosis. The subsequent diastolic dysfunction suggests that inhibition of matrix producing cells during hypertrophic stress is necessary to prevent functional and structural deterioration of the pressure-overloaded heart. Left ventricular mRNA expression profiles were compared between alpha-myosin heavy chain driven nitric oxide synthase 3 (alpha-MHC-NOS3) transgenic and wild type (WT) littermate mice at baseline and 10 weeks after transversal aortic constrcition-induced pressure-overload. Biological repeats: n=4, two males and two females, for each group and condition. Transgenic mice were backcrossed for seven generations (F7) to a C57Bl/6 N background and age and weight matched animals were used for microarray experiments.

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ERRalpha wt vs. ko hearts, baseline

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