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

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.

The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

“…Conversely, left ventricular hypertrophy (LVH) is found in over 60% of children and 37% in adults with SCD ( 389 , 390 ), with cardiopulmonary complications accounting for about 26% of deaths in adults with SCD ( 391 ). In this current issue and for the first time, our group investigated the expression of plasma and cardiac IL-6 and its inducibility by heme in Townes sickle cell (SS) mouse model ( 392 ). We observed significantly elevated cardiac IL-6 and direct heme induction of circulating and cardiac IL-6 transcripts and protein in SS mice compared to controls.…”

Extracellular Vesicles From Stored Red Blood Cells Convey Heme and Induce Spic Expression on Human Monocytes

“…Gbotsho et al recently demonstrated that when the plasma heme scavenging system is saturated, the circulating heme induces a cardiac expression of IL-6 in sickle cell mice through an Nfr2 independent pathway. Even though the underlying mechanisms of heme-induced IL-6 expression still need to be addressed, the authors suggested that this mechanism might involve the TLR-4-MyD88-AP-1 NF-ĸB axis ( 46 ).…”

Heme in Cardiovascular Diseases: A Ubiquitous Dangerous Molecule Worthy of Vigilance

“…Gbotosho et al recently suggested that heme induced IL-6 expression and cardiac hypertrophy in patients and mice with sickle cell disease (SCD) ( Gbotosho et al, 2020 ). Heme-laden erythrocyte membrane microparticles triggered rapid vaso-occlusions in kidneys and compromised microvascular dilation ( Camus et al, 2015 ).…”