Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Heart RNA-seq of control mice and a mouse model of cardiometabolic heart failure (HFpEF) treated with Rbm20 antisense oligonucleotides

ABSTRACT: We report the heart RNA-sequencing of control animals (C57BL/6N genetic background, wild type) and animals of a mouse model of cardiometabolic heart failure (HFpEF) treated or not with RBM20 antisense oligonucleotide. HFpEF was induced using a 2-hit regimen, in which male mice were fed with a high-fat diet (D12492, Research Diet Inc) and L-NAME 0.5g/L (nitric oxide synthase inhibitor) in drinking water, beginning at 3 months of age and continue for 22 weeks. Control male mice were fed with a control diet (D12450K, Research Diet Inc) and water without L-NAME This study aims to investigate the therapeutic effect of antisense oligonucleotide (ASO)-mediated downregulation of the cardiac splice factor RBM20 in HFpEF-like conditions. Adult mice were subcutaneously injected with 25 mg/kg/week for 6 weeks. RNA from left ventricular tissue was isolated using TRIzol followed by a clean-up with the QIAGEN RNA micro kit, cDNA libraries were generated using the Illumina TruSeq Stranded mRNA Sample Prep Kit 2x150 single-end sequenced on Illumina NovaSeq X Plus. The RNA-Sequencing analysis confirms that RBM20 ASO treatment increased the expression of compliant titin isoforms and improved diastolic function, even in the context of cardiometabolic stress.

INSTRUMENT(S): Illumina NovaSeq X

ORGANISM(S): Mus musculus

SUBMITTER: Stefan Meinke

PROVIDER: E-MTAB-14882 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Aims: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like Glucagon Like Peptide Receptor Agonist (GLP-1RA) and Sodium Glucose Transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide and a SGLT2i dapagliflozin. Methods&Results: Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high fat diet (HFD) for 12 weeks. After 8 weeks HFD, Angiotensin-II (ANGII), was administered for 4 weeks via osmotic mini-pumps. HFD+ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling and metabolic dysregulation with inflammation. The multiple-hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement lung congestion, and elevated blood pressures. Treatment with liraglutide attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapagliflozin treatment improved glucose handling, but had mild effects on the HFpEF phenotype. Conclusions: We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for treatment of HFpEF.

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Heart RNA-seq of control mice and a mouse model of cardiometabolic heart failure (HFpEF) treated with Rbm20 antisense oligonucleotides

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