Abstract 10279: Altered Myocardial Gene Expression in H2-kbm1 Mice with Orexinergic Dysfunction and Heart Failure

• Published in: Circulation (New York, N.Y.) N.Y.), 2021-11, Vol.144 (Suppl_1), p.A10279-A10279
• Main Authors: Stoller, Douglas, Dhar, Kajari, Basma, Hesham, Bonasera, Stephen J, Lowes, Brian D
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.144.suppl_1.10279

IntroductionMice carrying a homozygous frameshift mutation of the class I major histocompatibility antigen H2-K1 (H2-Kbm1) exhibit impaired development of hypothalamic orexinergic neurons. Similar to mice lacking the hypocretin (orexin) 2 receptor, H2-Kbm1 mice develop dilated cardiomyopathy and systolic heart failure (HF) from an early age. Previous studies suggest response to orexinergic signaling is predictive of patient response to current HF pharmacotherapeutic regimes. Our goal was to characterize the myocardial gene expression profiles of H2-Kbm1 mice. MethodsRNA was isolated from mice hearts (wild type n=5, mutant n=7) via the Qiagen RNeasy Mini Kit. DNase treatment was done to limit contamination of genomic DNA. Gene expression was measured using Illumina nexteq500 and 550 sequencing systems from a DNA library generated via the NuGene library kit (10 ng RNA). RNA-seq data analyses including comparisons, volcano and heatmap plots were completed. ResultsH2-Kbm1 mice differentially express 398 myocardial genes compared to control mice. Ingenuity pathway analysis indicates that these genes are involved in necrosis of cardiac muscle (z-score -1.8), cell death (z-score 1.6), and cardiac contractility (z-score -4). Upstream signaling analysis suggest regulation by Mir-122 (z-score 2.4), DNMT3 A and B (z-score 3.3 and 2.5), VEGF (z-score 4.6) and rosiglitazone (z-score -6.8). Canonical pathway analysis is shown in Figure 1. ConclusionH2-Kbm1 mice develop heart failure with marked myocardial transcriptional abnormalities that lead to impaired cardiac contraction and cell death. Differentially expressed genes are predominantly involved in mitochondrial function, oxidative phosphorylation, sirtuin signaling and the TCA cycle. Regulation of these genes is associated with miR-122, DNA methylations by DNMT3 A & B, VEGF and rosiglitazone signaling. The orexin pathway is a potential target for heart failure therapeutics.