New Insights in to Molecular Therapeutic Mechanism of Statin Action in Heart Failure: Use of High-Throughput Transcriptome Analysis

Abstract

Background and objective: The etiology of heart failure (HF) is multifactorial and a variety of mediators are involved in its progression. Thus, elucidation of transcriptome complexity and understanding the functions of differentially expressed genes, together with therapeutic molecular mechanisms underlying development of HF, are a major focus of HF research. A recent metaanalysis demonstrated that statin therapy reduced the risk of hospitalization and death due to HF. Methods and results: We first performed global cardiac transcriptome analysis in a canine model of tachycardia-induced HF using next generation genome sequencers; secondly we evaluated the effects of a statin, pitavastatin (0.3 mg/kg, n=6), on cardiac function and gene expressions in HF. A total of 426 genes were differentially expressed, 401 of which were up-regulated in failing heart compared to normals. We identified the ten most changed pathways which included angiopoietin receptor Tie 2, T cell receptor and CXCR4 signaling pathways. Despite an absence of differences in fractional shortening, pitavastatin significantly lowered elevations in left ventricular end-diastolic pressure and shortened prolongation of tau. Furthermore, pitavastatin suppressed up-regulation of expression of genes such as SRC, SHC1, VAV1, ELK1 and FLNA mRNA. Not only collagen types I and III, but also VI mRNA involved in maintaining structural integrity, were decreased compared with vehicle. These results indicate that statin may improve diastolic properties affecting cell proliferation, inflammation, oxidative stress, energy metabolism and extracellular matrix remodeling. Conclusion: High-throughput transcriptome analysis can provide new insights into cellular mechanisms underlying HF and therapeutic use of statin for treatment of HF.