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Pharmacological induction of heme oxygenase-1 by a triterpenoid protects neurons against ischemic injury.

ABSTRACT: Heme oxygenase-1 (HO-1) is an inducible Phase 2 enzyme that degrades toxic heme; its role in cerebral ischemia is not fully understood. We hypothesize that chemically induced HO-1 upregulation with the novel triterpenoid CDDO-Im (2-cyano-3,12 dioxooleana-1,9 dien-28-oyl imidazoline), a robust inducer of Phase 2 genes, protects neurons against ischemic injury.Using 3 different models of ischemia, including oxygen-glucose deprivation in neuronal cultures, global ischemia in rats, and focal ischemia in mice, we determined (1) whether CDDO-Im induces HO-1 expression and protects against ischemic injury; and (2) whether HO-1 inhibition disrupts the neuroprotective effect of CDDO-Im.CDDO-Im treatment (50-300 nmol/L) resulted in 8-fold HO-1 upregulation in cultured neurons and protected against oxygen-glucose deprivation. The protection was abolished when the cultures were transfected with nuclear factor (erythroid-derived 2) like-2-shRNA or coincubated with tin protoporphyrin IX, a specific HO-1 inhibitor. In the rat model of global ischemia, intracerebroventricular infusion of CDDO-Im (0.5-1.5 ?g) augmented HO-1 expression in hippocampal neurons and resulted in significant increases in CA1 neuronal survival after global ischemia. To further strengthen the clinical relevance of the CDDO-Im treatment, we tested its effects in the mouse model of temporary focal ischemia (60 minutes). Postischemic intraperitoneal injection of CDDO-Im (10-100 ?g) enhanced HO-1 expression and significantly reduced neurological dysfunction and infarct volume. Intracerebroventricular infusion of tin protoporphyrin IX reduced the neuroprotective effect of CDDO-Im against global and focal ischemia.CDDO-Im confers neuroprotection against ischemic injury by upregulating HO-1, suggesting that enhance of HO-1 expression may be a legitimate strategy for therapeutic intervention of stroke.

SUBMITTER: Zhang F

PROVIDER: S-EPMC3335928 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Pharmacological induction of heme oxygenase-1 by a triterpenoid protects neurons against ischemic injury.

Zhang Feng F Wang Suping S Zhang Meijuan M Weng Zhongfang Z Li Peiying P Gan Yu Y Zhang Lili L Cao Guodong G Gao Yanqin Y Leak Rehana K RK Sporn Michael B MB Chen Jun J

Stroke 20120329 5

<h4>Background and purpose</h4>Heme oxygenase-1 (HO-1) is an inducible Phase 2 enzyme that degrades toxic heme; its role in cerebral ischemia is not fully understood. We hypothesize that chemically induced HO-1 upregulation with the novel triterpenoid CDDO-Im (2-cyano-3,12 dioxooleana-1,9 dien-28-oyl imidazoline), a robust inducer of Phase 2 genes, protects neurons against ischemic injury.<h4>Methods</h4>Using 3 different models of ischemia, including oxygen-glucose deprivation in neuronal cultu ...[more]

PMID: 22461332

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Project description:BackgroundCellular senescence is a stable cell-cycle arrest induced by telomere shortening and various types of cellular stress including oxidative stress, oncogene activation, DNA damage etc. Heme oxygenase-1 (HO-1) is an inducible stress-response protein that plays antioxidant and anti-apoptotic effects. However, the role and underlying mechanisms of HO-1 in cellular senescence in heart are largely unknown.MethodsEchocardiography was employed to detect the effect of HO-1 on heart function in adult mice with myocardial infarction (MI) and aged mice. The senescence markers, p53, p16 and LaminB, were analyzed by western blot. The immunofluorescence and immunohistochemical staining were applied to analyze the expression level of p16. SA-?-Gal staining showed the level of cardiomyocyte senescence.FindingsWe found that hemin significantly induced the expression of HO-1, which notably suppressed cardiomyocyte senescence containing the secretion of senescence-associated secretory phenotype. Further studies showed that systemic HO-1 transgenic overexpression improved heart function by inhibiting aging-induced extracellular matrix deposition and fibrogenesis. More importantly, treatment of hemin improved heart function in MI mice. Furthermore, forced expression of HO-1 blunted cardiomyocyte senescence in natural aged mice and in primary cultured neonatal mouse cardiomyocytes.InterpretationOur study revealed that HO-1 improved heart function and attenuated cardiomyocyte senescence triggered by ischemic injury and aging. In addition, HO-1 induction alleviated H2O2-induced cardiomyocyte senescence. Finally, our study suggested a novel mechanism of HO-1 to play cardioprotective effect. FUND: This study was supported by the National Natural Science Foundation of China (81770284 to Hongli Shan); and the National Natural Science Foundation of China (81673425, 81872863 to Yuhong Zhou). The National Natural Science Foundation of China (81473213 to Chaoqian Xu). National Key R&D Program of China (2017YFC1307403 to Baofeng Yang), National Natural Science Foundation of China (81730012 to Baofeng Yang).

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Pharmacological induction of heme oxygenase-1 by a triterpenoid protects neurons against ischemic injury.

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Pharmacological induction of heme oxygenase-1 by a triterpenoid protects neurons against ischemic injury.

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