New Molecular Insights into Therapeutic Vascular Effects of Statin Action in Heart Failure Using High-throughput Transcriptome Analysis

Since the etiology of heart failure (HF) is multifactorial, elucidation of key functional molecules associated with HF is are a major focus of HF reserch. Endothelial function is significantly attenuated and reduced skeletal muscle blood flow and correlates with the severity of symptoms in HF. Improvement of its dysfunction is an important target in the treatment of HF. Many meta-analysis demonstrated that statin therapy reduced the risk of death due to cardiovascular events. 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 vascular endothelial function and gene expressions in the femoral artery. The mRNA sequence reads aligned with 15000 of the 21407 genes. We analyzed top twenty up regulated pathways which were associated with cell cycles, proliferation, inflammation and oxidative stress. Pitavastatin significantly improved femoral blood flow responses by acetylcholine(HF 92.4 ± 6.4 ml/min vs pitavastatin 144.3 ± 9.8 P < .05). The agent suppressed the levels of upregulated p53, Cyclin dependent kinase1, BCL3, RELA, NFKB, IL-6, and SOCS3 mRNAs expressions. Improved endothelial dysfunction in HF with the statin was closely linked with changes in those transcription factors expressions. We can conclude that high-throughput transcriptome analysis can provide new insights into cellular mechanisms underlying HF and therapeutic use of statin for treatment of HF.