Heme Oxygenase‐1 May Affect Cell Signalling via Modulation of Ganglioside Composition

Abstract

Heme oxygenase 1 (Hmox1), a ubiquitous enzyme degrading heme to carbon monoxide, iron, and biliverdin, is one of the cytoprotective enzymes induced in response to a variety of stimuli, including cellular oxidative stress. Gangliosides, sialic acid-containing glycosphingolipids expressed in all cells, are involved in cell recognition, signalling, and membrane stabilization. Their expression is often altered under many pathological and physiological conditions including cell death, proliferation, and differentiation. The aim of this study was to assess the possible role of Hmox1 in ganglioside metabolism in relation to oxidative stress. The content of liver and brain gangliosides, their cellular distribution, and mRNA as well as protein expression of key glycosyltransferases were determined in Hmox1 knockout mice as well as their wild-type littermates. To elucidate the possible underlying mechanisms between Hmox1 and ganglioside metabolism, hepatoblastoma HepG2 and neuroblastoma SH-SY5Y cell lines were used for in vitro experiments. Mice lacking Hmox1 exhibited a significant increase in concentrations of liver and brain gangliosides and in mRNA expression of the key enzymes of ganglioside metabolism. A marked shift of GM1 ganglioside from the subsinusoidal part of the intracellular compartment into sinusoidal membranes of hepatocytes was shown in Hmox1 knockout mice. Induction of oxidative stress by chenodeoxycholic acid in vitro resulted in a significant increase in GM3, GM2, and GD1a gangliosides in SH-SY5Y cells and GM3 and GM2 in the HepG2 cell line. These changes were abolished with administration of bilirubin, a potent antioxidant agent. These observations were closely related to oxidative stress-mediated changes in sialyltransferase expression regulated at least partially through the protein kinase C pathway. We conclude that oxidative stress is an important factor modulating synthesis and distribution of gangliosides in vivo and in vitro which might affect ganglioside signalling in higher organisms.

Nitric Oxide-Scavenging, Anti-Migration Effects, and Glycosylation Changes after Hemin Treatment of Human Triple-Negative Breast Cancer Cells: A Mechanistic Study

“…Moreover, the significant effects after cell treatment with DETA-NO and hemin relate to the enhanced uptake of hemin following its nitrosylation, as we reported before . These results, supported by the previous findings on the disruption of surface sialylation in hemin-treated erythrocyte and the inhibitory effects of upregulated HOX-1 in response to hemin, explain the decrease in fluorescence intensity in response to surface proteins with α-2,3-linked sialic acids. Hemin enhanced the expression of HOX-1, particularly in the presence of • NO.…”

Gangliosides and Neuroblastomas

“…NEU4 can also catalyze hydrolysis of ganglioside sialic acid residues and is expressed to about the same extent as NEU3 in the brain [55]. However, the intracellular location of the enzymes differs, with NEU4 sialyltransferase activity rAW 264.7 macrophage [80] Human neuroblastoma (NB) cells [81] GM2…”

Drug-Repurposing Strategy for Dimethyl Fumarate

“…Heme degradation by HO-1 reduces oxidative stress, heme being a promoter of ROS production, and biliverdin and carbon monoxide antioxidants [ 20 ]. Hmox1 −/− mice are characterized by a very high perinatal lethality and a very severe form of anemia due to low levels of serum iron [ 21 , 22 , 23 ].…”