Abstract
Heme oxygenase-1 (HO-1) has been reported to protect against oxidation and inflammation in atherosclerosis. It remains unclear how the immune system participates in the cytoprotective function of HO-1 in the context of atherosclerosis. In this study, we attempted to investigate the potential effect of a HO-1 inducer, hemin, and a HO-1 inhibitor, Tin-protoporphyrin IX (SnPP), on the progression of atherosclerosis in ApoE deficient mice. Using mass cytometry, 15 immune cell populations and 29 T cell sub-clusters in spleen and peripheral blood were thoroughly analyzed after hemin or SnPP treatment. SnPP elevated risk factors of atherosclerosis, whereas hemin reduced them. In-depth analysis showed that hemin significantly modified the immune system in both spleen and peripheral blood. Hemin increased dendritic (DC) and myeloid-derived suppressor cells (MDSCs), but decreased natural killer (NK) cells. An opposite effect was observed with SnPP treatment in terms of NK cells. NK cells and MDSCs were positively and negatively correlated with total cholesterol and low-density lipoprotein, respectively. Moreover, the T cell profiles were significantly reshaped by hemin, whereas only minor changes were observed with SnPP. Several hemin-modulated T cell clusters associated with atherosclerosis were also identified. In summary, we have unraveled an important regulatory role for HO-1 pathway in immune cell regulation and atherosclerosis. Our finding suggests that modulating HO-1 signaling represents a potential therapeutic strategy against atherosclerosis.
Highlights
Heme oxygenase-1 (HO-1) is a well-characterized inducible isoform of the rate-limiting monoxide, ferrous iron, and biliverdin
ApoE-/- mice were simultaneously intraperitoneally injected with HO-1 inducer hemin (Hemin group, 51280, Sigma, 5 mg/kg/d, n 6) or HO-1 inhibitor SnPP (SnPP group, B6432, APExBIO, 10 mg/kg/d, n 10) or vehicle (Control group, n 8) every other day for 10 weeks, during which time the body weight and the daily intake of food and water were monitored at weekly interval
In order to determine whether endogenous HO-1 system is involved in atherogenesis in vivo, we treated ApoE-/- mice on a western-type diet with well-proven HO-1 inducer hemin or inhibitor SnPP, respectively
Summary
Heme oxygenase-1 (HO-1) is a well-characterized inducible isoform of the rate-limiting monoxide, ferrous iron, and biliverdin. As a result of its antioxidant properties, HO-1 has cytoprotective effects in various pathological conditions such as atherosclerosis, diabetes, and occlusive vascular disease (Durante, 2011). Apolipoprotein E knockout (ApoE-/-) mice and low-density lipoprotein (LDL) receptor deficient (LDLr−/-) mice are widely used as murine models for atherosclerosis (Mukhopadhyay, 2013). Both in vivo and in vitro evidence have demonstrated the protective properties of HO-1 against atherosclerosis. Overexpression of HO-1 via adenovirus-mediated gene transfer in vascular cells attenuates the development of atherosclerosis in ApoE-/- mice (Juan et al, 2001). As a chronic inflammatory disease, atherosclerosis is closely associated with immune modulation
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