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Identification of gene expression signatures for phenotype-specific drug targeting of cardiac remodeling

ABSTRACT: Objectives Transcriptome analysis of the left ventricle (LV) aimed to identify targets for prevention of myocardial fibrosis (MF). Background MF causing heart failure with reduced ejection fraction is generated by different pathological mechanisms. We have designed two types of MF by using translational animal models: reactive interstitial MF and replacement fibrosis. Methods Domestic pigs were treated with either doxorubicin (DOX, n=5) or a liposomal encapsulation of doxorubicin-citrate (Myocet®, MYO, n=5) to generate cardiotoxicity-induced MF. For pressure overload-induced MF, we used artificial isthmus stenosis with stepwise developing myocardial hypertrophy and final fibrosis (Hyper, n=3). Volume-overload MF was developed in adverse remodeled LV after myocardial infarction (RemoLV, n=3). Sham interventions served as controls (Control, n=3). Myocardial samples from the anterior wall of groups DOX, MYO, Hyper and Control, and from the non-ischemic remodeled posterior wall of animals in group RemoLV were subjected to RNA-sequencing following transcriptional analysis.

ORGANISM(S): Sus scrofa

PROVIDER: GSE197049 | GEO | 2022/02/24

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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Identification of gene expression signatures for phenotype-specific drug targeting of cardiac remodeling

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