Cardiomyocyte-specific Nitric Oxide Synthase 3 Overexpression in Pressure-Overloaded Left Ventricle.
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ABSTRACT: 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 77±6 versus 65±2 ms-1, P=0.05), reduced heart weight-body weight ratio (HW/BW, 5.0±0.3 versus 5.8±0.1, P<0.05), and cardiomyocyte width than WT (14.9±0.4 vs 16.7±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.
ORGANISM(S): Mus musculus
PROVIDER: GSE37597 | GEO | 2016/01/15
SECONDARY ACCESSION(S): PRJNA162561
REPOSITORIES: GEO
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