Abstract 11988: Next Generation Sequencing of Cardiac Gene Expression Changes Associated With Heart Failure in Chronic Inflammation Inhibition
Since a variety of gene alternations are involved in heart failure (HF), identifying key functional molecules associated with HF is a challenging task. Therefore, we investigated the global transcriptome analysis of left ventricle (LV) from tachycardia induced HF dogs using next generation genome sequencers. The mRNA sequence reads aligned with ~15000 of the 21407 genes using the human genome19 database. The analysis identified significantly up-regulated genes associated with inflammation such as Rel A, STAT 3, RIPK2, CDKN1, TNF-alpha, interleukin (IL) and p53 related pathways and collagen type 4, which regulate cell cycles of inflammatory cells and fibroblast. These data suggest chronic inflammation induced by those novel genes may affect cardiac remodelling and inhibition of these effects may become one of the strategies to treat HF. Thus, we focused on cardiac chymase activity that is stored in the mast cells recruited by stem cell factor and affects chronic inflammation closely linked with cardiac remodelling. We examined therapeutic effects of a chymase inhibitor (ChyI 0.3mg/kg/day, n=7) on cardiac structural changes and gene expressions in failing dogs’ heart. In HF, the number of chymase-degranulated cells evaluated by chymotrypsin staining increased in the LV compared with the normal group, however, ChyI significantly decreased that cell density. ChyI significantly suppressed the IL-6, Rel A, STAT 3, CDKN1, RIPK2, TNF-alpha and p-53 mRNA levels in the cardiac tissue. Not only collagen type 1,3 but also type 4 mRNA involved in maintaining the structural integrity were decreased compared with the vehicle. ChyI suppressed fibrosis in LV evaluated with picrosirius red stain (% collagen volume fraction; 1.1, Normal; 4.6, ChyI; vs 7.1%, Vehicle; P<0.05, respectively). Despite no significant differences in blood pressure, ChyI shortened the prolongation of tau (22, Normal; 35, ChyI; vs 50 msec, Vehicle; P<0.05, respectively) and decreased LV end-diastolic pressure. We can conclude that the global transcriptome analysis can provide new insights into cellular mechanisms and therapeutic effects of ChyI in HF.
Author Disclosures: T. Matsumoto: None. A. Wada: None. M. Fujii: None. A. Taniguchi: None. K. Mori: None. Y. Tamagawa: None. T. Isono: None. M. Horie: None.
- © 2014 by American Heart Association, Inc.