Astrocyte Overexpression of Heme Oxygenase-1 Improves Outcome After Intracerebral Hemorrhage

Abstract

Background and Purpose Heme oxygenase-1 (HO-1) catalyzes the rate-limiting reaction of heme breakdown, and may have both antioxidant and pro-oxidant effects. In prior studies, HO-1 overexpression protected astrocytes from heme-mediated injury in vitro. In the present study, we tested the hypothesis that selective astrocyte overexpression of HO-1 improves outcome after intracerebral hemorrhage (ICH). Methods Male and female transgenic mice overexpressing human HO-1 driven by the GFAP promoter (GFAP.HMOX1) and wild-type controls received striatal injections of autologous blood (25 μl). Blood-brain barrier disruption was assessed by Evans blue assay and striatal cell viability by MTT assay. Neurological deficits were quantified by digital analysis of spontaneous cage activity, adhesive removal, and elevated body swing tests. Results Mortality rate for wild-type mice was 34.8% and was similar for males and females; all GFAP.HMOX1 mice survived. Striatal Evans blue leakage at 24 hours was 23.4+/−3.2 ng in surviving WT mice, compared with 10.9+/−1.8 ng in transgenics. Peri-hematomal cell viability was reduced to 61±4% of contralateral at 3 days in WT mice, v. 80±4% in transgenics. Focal neurological deficits were significantly reduced in GFAP.HMOX1 mice, and spontaneous cage activity was increased. Conclusions Selective HO-1 overexpression in astrocytes reduces mortality, blood-brain barrier disruption, peri-hematomal cell injury, and neurological deficits in an autologous blood injection ICH model. Genetic or pharmacologic therapies that acutely increase astrocyte HO-1 may be beneficial after ICH.

Astrocyte heme oxygenase-1 reduces mortality and improves outcome after collagenase-induced intracerebral hemorrhage

“…Consistent with prior observations (Chen-Roetling et al, 2015), striatal ICH increased native HO-1, as measured by mouse-specific ELISA. Human HO-1 in GFAP.HMOX1 striata was 4–5-fold greater than mouse HO-1, and was not altered by collagenase injection (Fig.…”

“…Genotype was verified by PCR using previously-published primers (Chen-Roetling et al, 2015). HO-1 overexpression specifically in astrocytes has previously been confirmed by double immunofluorescence staining (Chen-Roetling et al, 2015). Mice were used for experiments when 3–6 months old.…”

“…In a prior study, HO-1 overexpression that was restricted to GFAP+ astrocytes markedly reduced mortality and behavioral deficits after striatal injection of autologous blood (Chen-Roetling et al, 2015). In light of these robust results, determination of the consistency of this effect across ICH models seemed warranted.…”

The Indispensable Roles of Microglia and Astrocytes during Brain Development

“…Some claim however that in the retina astrocyte-derived VEGF is only important in hypoxia-induced pathological angiogenesis and not in developmental angiogenesis under physiological conditions (Weidemann et al, 2010). In addition to VEGF, astrocytes were shown to be capable of secreting other angiogenic molecules such as angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), endothelin-1 (ET-1) and oxygenase-1 (HO-1; Nakamura-Ishizu et al, 2012; Li et al, 2013; Hammond et al, 2014; Chen-Roetling et al, 2015). Apart from the secretion of angiogenic molecules, astrocytes are capable of expressing axonal guidance molecules and growth factors, as described in chapter 5.2, of which some were shown to affect vessel sprouting as well (Basile et al, 2004; Lu et al, 2004; Torres-Vázquez et al, 2004; Carmeliet and Tessier-Lavigne, 2005).…”

Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage

“…In order to determine if selective astrocyte HO-1 per se is protective after ICH, transgenic mice expressing human HO-1 driven by the GFAP promoter were tested in the blood injection ICH model [147]. HO-1 expression in ipsilateral striata at 7 hours after blood injection was increased over sevenfold in transgenics, and was localized predominantly to perivascular astrocytes.…”