GSE112055
Evaluation of PDE5A and PDE9A Inhibition Impacts on Cardiac mRNA Expression in a Mouse Pressure-Overload-Induced Heart Failure Model
Purpose: This study aimed to determine how two drugs, both ultimately activating the same effector kinase, may differentially modulate mRNA expression in a mouse model of cardiac pressure-overload-induced heart failure. Methods: C57Bl/6J mice were subjected to sham or TAC surgeries to induce cardiac pressure-overload and subsequent heart failure. After one week, treatment with either a PDE5A inhibitor (PDE5A-I) or PDE9A inhibitor (PDE9A-I) was initiated and continued for 4 weeks, with cardiac functional measurements to assess treatment efficacy occurring weekly. At 5 weeks after surgery, mice were sacrificed and myocardium collected. Left ventricular myocardium was used for RNA isolation and subsequent mRNA sequencing on an Illumina HiSeq 2500. Data was aligned using HISAT2 v2.0.5, and transcript counts were quantified using RSEM v1.3.0. Count data was further analyzed for differential expression using Bioconductor's DESeq2 package (v1.18.1). Results and Conclusions: Our study details how two treatments, both targeting the same kinase and with similar phenotypic improvements, result in similar pathways being altered, albeit often through modulation of different genes in the pathway. Our data demonstrates how subcellular compartmentalization of signaling pathway components can differentially impact gene expression, while still ultimately converging on similar overall effects on modification of cellular signaling. Overall design: Myocardial mRNA profiles were generated for C57Bl6/J mice subjected to cardiac pressure-overload or sham surgeries, and concomitantly treated with either a PDE5A or PDE9A inhibitor. Sequencing was performed on an Illumina HiSeq 2500 with an n of 5-6 per group.