Abstract 202: Genetic Ablation of Interleukin-18 Does Not Attenuate Hypobaric Hypoxia-Induced Right Ventricular Dysfunction
Interleukin-18 (IL-18), a pro-inflammatory cytokine, has been implicated in pathogenic left ventricular hypertrophy and is elevated in plasma of heart failure patients. However, IL-18 blockade strategies in animal models of heart disease have been conflicting. Accordingly, the purpose of these experiments was to determine whether genetic ablation of IL-18 would protect male and female mice against hypobaric hypoxia-induced right ventricular (RV) dysfunction. We hypothesized that IL-18 knockout mice (KO) would be protected while wild type (WT) mice would show significant right ventricular dysfunction in response to exposure to hypobaric hypoxia (HH). KO and WT mice were exposed to HH for 7 weeks, and control (CO) mice were exposed to normoxic, ambient air. Following echocardiography, the RV was dissected and flash frozen for biochemical analyses. 7 week HH exposure trended toward an increase in IL-18 mRNA (p=0.08) in RV from WT mice. However, contrary to our hypothesis, IL-18 KO mice were not protected against HH-induced RV dysfunction, as evidenced by higher RV weights, elevated RV systolic pressure, and increased RV anterior wall thickness compared to normoxic KO mice. Importantly, these measurements were not significantly different from WT HH mice. Biochemical analyses suggest HH RV underwent early remodeling, as no changes were observed at the molecular level in the RV of HH mice compared to CO in either KO or WT animals. Compensatory upregulation of the other pro-inflammatory cytokines IL-2 and SDF-1 may have contributed to the lack of protection in IL-18 KO animals. These data suggest IL-18 signaling is not necessary for hypobaric hypoxia induced RV dysfunction, and blockade of IL-18 is not a viable therapeutic strategy in this model.
Author Disclosures: D.R. Bruns: None. P.M. Buttrick: None. L.A. Walker: None.
- © 2015 by American Heart Association, Inc.