Heme modulates smooth muscle cell proliferation and migration via NADPH oxidase: A counter-regulatory role for heme oxygenase system

Abstract

Accumulation of vascular smooth muscle cells (VSMC) in response to inflammatory stimuli is a key event in atherogenesis, which commonly occurs in sinuous vessels with turbulent blood flow what leads to hemolysis and consequent free heme accumulation, a known pro-oxidant and pro-inflammatory molecule. In this work, we investigated the effects of free heme on VSMC, and the molecular mechanisms underlying this process. Free heme induces a concentration-dependent migration and proliferation of VSMC which depends on the production of reactive oxygen species (ROS) derived from NADPH oxidase (NADPHox) activity. Additionally, heme activates redox-sensitive proliferation-related signaling routes, such as mitogen activated protein kinase (MAPK) and NF-κB, and induces heme oxygenase-1 (HO-1) expression. NADPHox-dependent proliferative effect of heme seems to be endogenously modulated by HO since the pretreatment of VSMC with HO inhibitors potentiates heme-induced proliferation and, in parallel, increases ROS production. These effects were no longer observed in the presence of heme metabolites, carbon monoxide and biliverdin. The data indicate that VSMC proliferation induced by heme is endogenously modulated by a critical counter-regulatory crosstalk between NADPHox and HO systems.

Heme modulates intestinal epithelial cell activation: involvement of NADPHox-derived ROS signaling

“…It has also been shown that heme is able to activate redox-sensitive pathways in vascular smooth muscle cells (15,21), supporting the link between heme and NADPHox activation. The NAPDHox family consists of seven members (NOX1-5 and DUOX1-2) that are distinctly expressed by different tissues.…”

New Insights into Intracellular Locations and Functions of Heme Oxygenase-1

“…More recently, HMOX1 induction or administration of heme degradation products has been found to have beneficial vascular effects, in part, via regulation of free heme and NADPH oxidases (116). NADPH oxidases generate superoxide and H 2 O 2 derived from it that not only play important roles in host defense and cell signaling but can also lead to oxidative stress and inflammation.…”

Protein aggregation as a cellular response to oxidative stress induced by heme and iron

“…Compelling evidence from the literature shows that many of the inflammatory and cytotoxic effects exerted by heme are mediated by ROS that can be generated by enzymatic as well as nonenzymatic reactions (9,17,27,28). As an important source of cellular stress, an excess of ROS also has been implicated as a trigger for protein aggregation (29,30).…”