Genetic ablation of interleukin-18 does not attenuate hypobaric hypoxia-induced right ventricular hypertrophy

Am J Physiol Lung Cell Mol Physiol. 2016 Mar 15;310(6):L542-50. doi: 10.1152/ajplung.00166.2015. Epub 2016 Jan 8.


Interleukin-18 (IL-18), a proinflammatory cytokine, has been implicated in pathologic left ventricular hypertrophy and is elevated in plasma of heart failure patients. However, IL-18 blockade strategies have been conflicting. The purpose of these experiments was to determine whether genetic ablation of IL-18 would protect mice against hypobaric hypoxia (HH)-induced right ventricular (RV) hypertrophy, a condition in which chamber-specific inflammation is prominent. We hypothesized that IL-18 knockout (KO) mice would be protected while wild-type (WT) mice would demonstrate RV hypertrophy in response to HH exposure. KO and WT mice were exposed to HH for 7 wk, and control mice were exposed to normoxic ambient air. Following echocardiography, the RV was dissected and flash-frozen for biochemical analyses. HH exposure increased IL-18 mRNA (P = 0.08) in RV from WT mice. Genetic ablation of IL-18 mildly attenuated RV hypertrophy as assessed by myocyte size. However, IL-18 KO mice were not protected against HH-induced organ-level remodeling, as evidenced by higher RV weights, elevated RV systolic pressure, and increased RV anterior wall thickness compared with normoxic KO mice. These RV changes were similar to those seen in HH-exposed WT mice. Compensatory upregulation of other proinflammatory cytokines IL-2 and stromal cell-derived factor-1 was seen in the HH-KO animals, suggesting that activation of parallel inflammatory pathways might mitigate the effect of IL-18 KO. These data suggest targeted blockade of IL-18 alone is not a viable therapeutic strategy in this model.

Keywords: IL-18; cardiac; pulmonary hypertension; right ventricle.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / metabolism
  • Collagen / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gene Expression
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / metabolism
  • Hypertrophy, Right Ventricular / etiology
  • Hypertrophy, Right Ventricular / genetics*
  • Hypertrophy, Right Ventricular / metabolism
  • Hypoxia / complications*
  • Hypoxia / genetics
  • Hypoxia / metabolism
  • Interleukin-18 / genetics*
  • Interleukin-18 / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / metabolism
  • Myocardium / pathology
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Ventricular Remodeling


  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Interleukin-18
  • Collagen
  • Extracellular Signal-Regulated MAP Kinases