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Heme Induces IL-6 and Cardiac Hypertrophy Genes Transcripts in Sickle Cell Mice

Authors
  • Gbotosho, Oluwabukola T.1, 2
  • Kapetanaki, Maria G.2, 3
  • Ghosh, Samit1, 4
  • Villanueva, Flordeliza S.5
  • Ofori-Acquah, Solomon F.1, 2, 4, 6
  • Kato, Gregory J.1, 2
  • 1 Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA , (United States)
  • 2 Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA , (United States)
  • 3 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA , (United States)
  • 4 Department of Medicine, Center for Translational and International Hematology, School of Medicine, University of Pittsburgh, Pittsburgh, PA , (United States)
  • 5 Center for Ultrasound Molecular Imaging and Therapeutics, Heart and Vascular Institute, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA , (United States)
  • 6 School of Biomedical and Allied Health Sciences, University of Ghana, Accra , (Ghana)
Type
Published Article
Journal
Frontiers in Immunology
Publisher
Frontiers Media SA
Publication Date
Aug 21, 2020
Volume
11
Identifiers
DOI: 10.3389/fimmu.2020.01910
PMID: 32973791
PMCID: PMC7473032
Source
PubMed Central
Keywords
License
Unknown

Abstract

Emerging data indicate that free heme promotes inflammation in many different disease settings, including in sickle cell disease (SCD). Although free heme, proinflammatory cytokines, and cardiac hypertrophy are co-existing features of SCD, no mechanistic links between these features have been demonstrated. We now report significantly higher levels of IL-6 mRNA and protein in hearts of the Townes sickle cell disease (SS) mice (2.9-fold, p ≤ 0.05) than control mice expressing normal human hemoglobin (AA). We find that experimental administration of heme 50 μmoles/kg body weight induces IL-6 expression directly in vivo and induces gene expression markers of cardiac hypertrophy in SS mice. We administered heme intravenously and found that within three hours plasma IL-6 protein significantly increased in SS mice compared to AA mice (3248 ± 275 vs. 2384 ± 255 pg/ml, p ≤ 0.05). In the heart, heme induced a 15-fold increase in IL-6 transcript in SS mice heart compared to controls. Heme simultaneously induced other markers of cardiac stress and hypertrophy, including atrial natriuretic factor (Nppa; 14-fold, p ≤ 0.05) and beta myosin heavy chain (Myh7; 8-fold, p ≤ 0.05) in SS mice. Our experiments in Nrf2-deficient mice indicate that the cardiac IL-6 response to heme does not require Nrf2, the usual mediator of transcriptional response to heme for heme detoxification by heme oxygenase-1. These data are the first to show heme-induced IL-6 expression in vivo , suggesting that hemolysis may play a role in the elevated IL-6 and cardiac hypertrophy seen in patients and mice with SCD. Our results align with published evidence from rodents and humans without SCD that suggest a causal relationship between IL-6 and cardiac hypertrophy.

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