Abstract 18175: Cytoglobin-Defiencient Mice Develop Maladaptive Cardiac Remodeling After Ischemia-Reperfusion Injury Due to Alterations in NF-kB Signaling
Cytoglobin (Cygb) is a stress-responsive hemoprotein expressed in cardiomyocytes. Data from our laboratory indicate Cygb is able to translocate to the nucleus under stress and one mechanism by which it is able to exert its cytoprotective effect is by serving as a repressor of p53 transcriptional activity. In a model of ischemia-reperfusion (IR), Cygb transcript levels within wild-type hearts peak 2 days post-IR injury. We hypothesize that Cygb modulates cardiac remodeling following IR injury by effecting redox sensitive signaling pathyways (p53, NF-κB, etc). To test our hypothesis, we generated mice with cardiac-specific deletion of Cygb (Cygb+/-). These mice are viable with normal cardiac function under baseline conditions [ECHO: FS(%) 70±0.05 vs 72±0.05, Cygb+/- vs control (Ctrl); p=NS, n=12]. However, Cygb+/- mice develop worse cardiac remodeling 1 month post-IR injury [FS(%) 35±0.05 vs 59±0.05, p<0.005, n=8; %Fibrosis of LV 40 vs 20, p<0.05, n=4; Cygb+/- vs Ctrl] with evidence of increased cardiomyocyte cell death (TUNEL 8.0±0.5 vs 2.0±0.5 cells per unit area, Cygb+/- vs Ctrl; p<0.05, n=4). In vitro assays utilizing small interference RNA targeting Cygb also support the importance of Cygb in maintaining cardiomyocyte viability under hypoxic conditions (%Viability 47.34±0.05 vs 57.14±0.05, hypoxic siCygb H9C2 vs hypoxic Ctrl siRNA H9C2 cells; p<0.05, n=6). A transcriptome analysis of the NF-κB signaling pathway (60 genes including IL-6, Myd88, CSF2, and TLR3) revealed a global downregulation in expression of NF-κB target genes in hypoxic H9C2 cells and IR-injured Cygb+/- hearts. Utilizing in vitro assays (Luc assays, etc) NF-κB activity in siCygb H9C2 cells was decreased in a p53-dependent manner. This data was confirmed by demonstrating decreased NF-κB activity in 2 day post-IR injured Cygb+/- hearts. Collectively, our data suggests Cygb modulates cardiac remodeling post-IR injury by affecting NF-κB signaling via a p53-dependent mechanism.
- © 2013 by American Heart Association, Inc.